Methods for treating hepatitis B virus infections using NS5A, NS5B or NS3 inhibitors

ABSTRACT

Provided are methods for treating hepatitis B virus infections by administering a NS5A inhibitor, NS5B inhibitor, a NS3 inhibitor, or combinations thereof.

This application claims the benefit under 35 U.S.C. § 119(e) of the U.S.Provisional Application Ser. No. 62/342,787 filed May 27, 2016, thecontent of which is hereby incorporated by reference in its entirety.

FIELD

The disclosure relates generally to methods, compounds and compositionsfor treating hepatitis B virus infections.

BACKGROUND

Worldwide, approximately 400 million people are living with chronichepatitis B infection (HBV). HBV is an enveloped, partiallydouble-stranded DNA virus. HBV is an infectious disease that affects theliver. Initial symptoms of infection may include vomiting, jaundice,lethargy, dark urine, and abdominal pain. Chronic HBV infection canresult in cirrhosis and liver cancer. Currently available therapies caninhibit replication of the virus and minimize liver damage; however,there are no currently available therapies that can clear an HBVinfection.

HBV surface antigen (HBsAg) is a protein located in the HBV envelope. Itallows HBV virion entry into host cells by binding to the hepatocytesodium-taurocholate cotransporting polypeptide (NTCP) receptor. HBsAgmay also function as a tolerogen, suppressing immune elimitation ofinfected cells. Total HBsAg loss and seroconversion are rarely achievedin chronically infected patients. Inhibiting HBsAg secretion and/orproduction is thus believed to be a strategy for the treatment of HBVinfection, including chronic HBV infection. (Wieland, S. F. & F. V.Chisari, J. Virol. (2005), 79, 9369-80; Woltman et al. PLoS One (2011),6, e15324; Op den Brouw et al. Immunology (2009b), 126, 280-89).

There remains a need to develop effective treatments for hepatitis Binfection.

SUMMARY

It has now been discovered that when a patient is administeredinhibitors of certain HCV nonstructural proteins, such as a NS5Ainhibitor, a NS5B inhibitor, a NS3 inhibitor, or combinations thereof,the HBV surface antigen (HBsAg) is decreased, thereby treating thepatient's HBV infection. Therefore, in one embodiment, is provided amethod of treating HBV infection in a human in need thereof, comprisingadministering to the patient an effective amount of a NS5A inhibitor. Inone embodiment, is provided a method of treating HBV infection in ahuman in need thereof, comprising administering to the patient aneffective amount of a NS5B inhibitor. In one embodiment, is provided amethod of treating HBV infection in a human in need thereof, comprisingadministering to the patient an effective amount of a NS3 inhibitor. Inyet another embodiment, the patient is administered both an effectiveamount of a NS5A inhibitor and a NS5B inhibitor and optionally a NS3inhibitor. In one embodiment, the patient is further administeredanother anti-HBV agent, such as reverse transcriptase inhibitors. In oneembodiment, the patient is co-infected with human immunodeficiency virus(HIV). In one embodiment, the patient is not co-infected with hepatitisC virus (HCV). In one embodiment, the NS5A inhibitor is ledipasvir orvelpatasvir. In one embodiment, the NS5B inhibitor is sofosbuvir ormericitabine. In one embodiment, the NS5A inhibitor is ledipasvir andthe NS5B inhibitor is sofosbuvir. In one embodiment, the NS3 inhibitoris voxilaprevir. In one embodiment, the anti-HBV agent is tenofovir.

In one embodiment, the patient is administered a combination of eitherledipasvir or velpatasvir, together with sofosbuvir and voxilaprevir. Inone embodiment, the patient is administered a combination of eitherledipasvir or velpatasvir, together with sofosbuvir and tenofovir.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the reduction of HBsAg in a study where 8 pateints wereadministered a fixed dose combination of ledipasvir and sofosbuvir.

FIG. 2 shows the change in HBV DNA and HBsAG at week 4 and week 8timepoints after administration of a fixed dose combination ofledipasvir and sofosbuvir.

FIG. 3 shows the HBsAg and HBV DNA kinetics at various timepoints afteradministration of a fixed dose combination of ledipasvir and sofosbuvir.

FIG. 4 shows the change from baseline in HBsAg after administration of afixed dose combination of ledispavir and sofosbuvir.

DETAILED DESCRIPTION

Reference will now be made in detail to certain embodiments of thedisclosure, examples of which are illustrated in the accompanyingdescription, structures and formulas. While the disclosure will bedescribed in conjunction with the enumerated embodiments, it will beunderstood that they are not intended to limit the disclosure to thoseembodiments. On the contrary, the disclosure is intended to cover allalternatives, modifications, and equivalents, which may be includedwithin the scope of the present disclosure.

I. METHODS

As stated above, it is discovered that administration of inhibitors ofcertain nonstructural proteins in the hepatitis C virus are useful inreducing HBV surface antigens, thereby treating HBV infected patients.

It is to be understood that the term “treatment” or “treating” means anyadministration of a compound(s) of the disclosure to a mammal (e.g. ahuman) having HBV for the purpose of: (i) preventing the disease, thatis, causing the clinical symptoms of the disease not to develop; (ii)inhibiting the disease, that is, arresting the development of clinicalsymptoms; and/or (iii) relieving the disease, that is, causing theregression of clinical symptoms.

Therefore, in one embodiment, is provided a method of treating HBVinfection in a human in need thereof, comprising administering to thepatient an effective amount of a NS5A inhibitor. In one embodiment, isprovided a method of treating HBV infection in a human in need thereof,comprising administering to the patient an effective amount of a NS5Binhibitor. In one embodiment, is provided a method of treating HBVinfection in a human in need thereof, comprising administering to thepatient an effective amount of a NS3 inhibitor. In one embodiment isprovided a method for treating a hepatitis B virus infection in a humanin need thereof comprising administering an effective amount of a NS5Ainhibitor and an effective amount of a NS5B inhibitor and optionally aNS3 inhibitor. In one embodiment, the NS5A inhibitor is ledipasvir orvelpatasvir. In one embodiment, the NS5A inhibitor is ledipasvir. In oneembodiment, the NS5B inhibitor is sofosbuvir or mericitabine. In oneembodiment, the NS5A inhibitor is ledipasvir and the NS5B inhibitor issofosbuvir. In this embodiment, the patient is administered about 90milligrams of ledipasvir and about 400 milligrams of sofosbuvir. Incertain embodiments, the inhibitors are administered together. In otherembodiments, the inhibitors are administered separately.

In one embodiment, the NS3 inhibitor is voxilaprevir.

In one embodiment, the patient is administered a combination of eitherledipasvir or velpatasvir, together with sofosbuvir and voxilaprevir.

In one embodiment, the patient is further administered another anti-HBVagent. In one embodiment, the patient is administered a NS5A inhibitorand an anti-HBV agent. In one embodiment, the patient is administered aNS5B inhibitor and an anti-HBV agent. In one embodiment, the patient isadministered a NS3 inhibitor and an anti-HBV agent. In one embodiment,the patient is adminstered a NS5A inhibitor, a NS5B inhibitor, ananti-HBV agent and optionally a NS3 inhibitor. In one embodiment, theNS5A inhibitor is ledipasvir or velpatasvir. In one embodiment, the NS5Ainhibitor is ledipasvir. In one embodiment, the NS5B inhibitor issofosbuvir or mericitabine. In one embodiment, the NS5A inhibitor isledipasvir and the NS5B inhibitor is sofosbuvir. In one embodiment, theanti-HBV agent is tenofovir alafenamide. In one embodiment, the NS3inhibitor is voxilaprevir. In one embodiment, the patient isadministered a combination of either ledipasvir or velpatasvir, withsofosbuvir, voxilaprevir and tenofovir alafenamide. In one embodiment,the patient is administered about 90 milligrams of ledipasvir, about 400milligrams of sofosbuvir and about 25 mg of tenofovir alafenamide. Incertain embodiments, the inhibitors are administered together. In otherembodiments, the inhibitors are administered separately.

In one embodiment, the patient is co-infected with humanimmunodeficiency virus (HIV). In one embodiment, the patient is notco-infected with hepatitis C virus (HCV).

In one embodiment, the inhibitor(s) inhibit HBsAG production orsecretion. In one embodiment, the inhibitor(s) inhibit HBV geneexpression. In one embodiment, the inhibitor(s) are useful for thetreatment or prophylaxis of HBV infection. In one embodiment, theinhibitor(s) inhibit HBV DNA production. In one embodiments, theinhibitor(s) inhibit HBV DNA replication.

In one embodiment is a pharmaceutical composition comprising a NS5Ainhibitor for use in treating a hepatitis B virus infection in a human.In one embodiment is a composition comprising a NS5A inhibitor for usein the preparation of a medicament useful in treating a hepatitis Bvirus infection in a human. In one embodiment, the composition furthercomprises another anti-HBV agent.

In one embodiment is a pharmaceutical composition comprising a NS5Binhibitor for use in treating a hepatitis B virus infection in a human.In one embodiment is a composition comprising a NS5B inhibitor for usein the preparation of a medicament useful in treating a hepatitis Bvirus infection in a human. In one embodiment, the composition furthercomprises another anti-HBV agent.

In one embodiment is a pharmaceutical composition comprising a NS3inhibitor for use in treating a hepatitis B virus infection in a human.In one embodiment is a composition comprising a NS3 inhibitor for use inthe preparation of a medicament useful in treating a hepatitis B virusinfection in a human. In one embodiment, the composition furthercomprises another anti-HBV agent.

In one embodiment is a pharmaceutical composition comprising a NS5Ainhibitor and a NS5B inhibitor and optionally a NS3 inhibitor for use intreating a hepatitis B virus infection in a human. In one embodiment, isa composition comprising a NS5A inhibitor and a NS5B inhibitor andoptionally a NS3 inhibitor for use in the preparation of a medicamentuseful in treating a hepatitis B virus infection in a human. In oneembodiment, the composition further comprises another anti-HBV agent.

II. COMPOUNDS

The protein products of the HCV gene include the non-structural proteinsNS2, NS3, NS4A and NS4B, and NS5A and NS5B. In HCV infected cells, NS5Ais produced as part of the viral polyprotein. Once cleaved from thepolyprotein, NS5A localizes to membranes where it binds to the newlysynthesized viral RNA and participates in genome replication, in partthrough interactions with the viral RNA-dependent RNA polymerase NS5B.NS5A inhibitors are compounds that target the HCV-encoded NS5A geneproduct. NS3 is a viral nonstructural protein that is 70 kDa cleavageproduct of the hepatitis C virus polyprotein. It acts as a serineprotease.

It should be noted that the term compound or inhibitor is usedinterchangeably throughout.

HCV NS5B polymerase is required for the synthesis of a double-strandedRNA from a single-stranded viral RNA that serves as a template in thereplication cycle of HCV. Inhibition of HCV NS5B polymerase preventsformation of the double-stranded HCV RNA. Examples of both NS5A, NS5B,and NS3 compounds are described below.

A. NS5A Inhibitors

In one embodiment, the NS5A inhibitor is a compound described in PCTPublication No. WO2010/132601, which is hereby incorporated by referencein its entirety. It is contemplated that the NS5A inhibitor may also beselected from compounds disclosed in U.S. Pat. No. 9,156,823; US2013/0309196 (WO 2013/173488); or US 2014/0178336 (or WO 2014/100500),all of which are incorporated by reference in their entirety.

In one embodiment, the NS5A inhibitor is a compound of Formula I(described in WO2010/132601):J-Y-J   Formula I

-   -   wherein:        -   Y is -L-L-, -M-W-M- or Y¹;        -   J is T-P—, —P-T or -J^(m);        -   W is a bond or —W^(r)—;        -   L is -M-A-, -A-M-, or -L^(n);        -   T is R9-Z—, —Z—R⁹, or -T^(p);        -   R⁹ is E-V-, or —V-E, or —R9^(q);        -   each A is selected from -A^(s);        -   each M is selected from -M^(t);        -   each P is selected from —P^(u);        -   each Z is selected from —Z^(v);        -   each V is selected from —V^(w);        -   each E is selected from -E^(x);        -   each m is 1        -   each n is 0, 1, 2, 3, 4, 5, 6, 7, 9, or 10;        -   each p is 1, 2, 3, 4, 5, 6, 7, or 8;        -   each q is 0, 1, 2, or 3;        -   each r is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,            16, 17, 18, 19, or 20;        -   each s is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,            15, 16, 17, 18, or 21;        -   each t is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11;        -   each u is 0, 1, 2, 3, 4, 5, 6, 7, 8, 10, 11, 12, 13, 14, 15,            16, 17, 18, or 19;        -   each v is 0, 1, 2, 3, 4, 5, or 6;        -   each w is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,            15, 16, 17, 18, 19, 20, 21, 22, 23, or 24;        -   each x is 0, 1, 2, 3, 4, 5, 6, or 7;        -   each y is 0, 1, or 2;        -   wherein P is connected to M, L, or Y^(y); A is connected to            A or L; M is connected to P or J; Z is connected to P; V is            connected to Z; and when W is a bond M is connected to M;    -   each J¹ is independently a fused bicyclic saturated, partially        unsaturated, or aromatic heterocyclic ring system that is        substituted with one or more —N(R^(L7))C(═O)OR^(L7), and that is        optionally substituted with one or more groups independently        selected from oxo, halo, —R^(L7), —OR^(L7), —SR^(L7), —CF₃,        —CCl₃, —OCF₃, —CN, —NO₂, —N(R^(L7))C(═O)R^(L7), —C(═O)R^(L7),        —OC(═O)R^(L7), —C(O)OR^(L7), —C(═O)NR^(L7), —S(═O)R^(L7),        —S(═O)₂OR^(L7), —S(═O)₂R^(L7), —OS(═O)₂OR^(L7), —S(═O)₂NR^(L7),        alkoxyalkyl, arylalkoxycarbonyl, halo, haloalkyl, hydroxyalkyl,        —NR^(a)R^(b), (NR^(a)R^(b))alkyl, and (NR^(a)R^(b))carbonyl;        -   each R^(L7) is independently —H, alkyl, aryl, arylalkyl, or            heterocycle;        -   R^(a) and R^(b) are independently selected from the group            consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl, aryl,            arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl,            heterocyclyl, and heterocyclylalkyl;    -   each L⁰ is independently:

-   -   -   wherein:            -   each R^(L2) is independently selected from hydrogen,                alkenyl, alkoxy, alkyl, halo, and haloalkyl; and            -   each aa is independently 1, 2, 3, or 4;

    -   each L¹ is independently:

-   -   -   wherein:            -   each R^(L2) is independently selected from hydrogen,                alkenyl, alkoxy, alkyl, halo, and haloalkyl;            -   each R^(L3) is independently selected from cyano, nitro,                SOR⁴, SO₂R⁴, -alkylSO₂R⁴, haloalkoxy, cyanoalkyl,                NR⁴SO₂R⁴, cycloalkyl, (halo)cycloalkyl, heterocycle,                (cycloalkyl)alkyl, (heterocycle)alkyl, wherein each                alkyl, heterocycle and cycloalkyl is optionally                substituted with one or more halo; and            -   each R⁴ is independently selected from H, alkyl,                haloalkyl, aryl, and arylalkyl;            -   each bb is 0, 1, 2, 3, or 4; each aa is 1, 2, 3, or 4;                and the sum of bb and aa is 1, 2, 3, or 4;

    -   each L² is independently:        -   wherein:

-   -   -   -   the phenyl ring shown in L² is optionally substituted                with one or more groups independently selected from                alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl,                arylalkoxycarbonyl, carboxy, formyl, halo, haloalkyl,                hydroxy, hydroxyalkyl, —NR^(a)R^(b), (NR^(a)R^(b))alkyl,                (NR^(a)R^(b))carbonyl, cyano, nitro, SOR⁴, SO₂R⁴,                -alkylSO₂R⁴, haloalkoxy, cyanoalkyl, NR⁴SO₂R⁴,                cycloalkyl, (halo)cycloalkyl, heterocycle,                (cycloalkyl)alkyl, (heterocycle)alkyl, wherein each                alkyl, heterocycle and cycloalkyl is optionally                substituted with one or more halo;

        -   each R^(L4) is independently —H, alkyl, aryl, arylalkyl, or            heterocycle;

        -   each R⁴ is independently selected from H, alkyl, haloalkyl,            aryl, and arylalkyl;

        -   R^(a) and R^(b) are independently selected from the group            consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl, aryl,            arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl,            heterocyclyl, and heterocyclylalkyl; and            -   each H1 is a 5 membered saturated, partially                unsaturated, or aromatic ring comprising one or more                heteroatoms.

    -   each L³ is independently a fused-bicyclic saturated, partially        unsaturated, or aromatic heterocyclic ring system that is        optionally substituted with one or more groups independently        selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl,        arylalkoxycarbonyl, carboxy, formyl, halo, haloalkyl, hydroxy,        hydroxyalkyl, —NR^(a)R^(b), (NR^(a)R^(b))alkyl,        (NR^(a)R^(b))carbonyl, cyano, nitro, SOR⁴, SO₂R⁴, -alkylSO₂R⁴,        haloalkoxy, cyanoalkyl, NR⁴SO₂R⁴, cycloalkyl, (halo)cycloalkyl,        heterocycle, (cycloalkyl)alkyl, (heterocycle)alkyl, wherein each        alkyl, heterocycle and cycloalkyl is optionally substituted with        one or more halo;        -   each R⁴ is independently selected from H, alkyl, haloalkyl,            aryl, and arylalkyl; and        -   R^(a) and R^(b) are independently selected from the group            consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl, aryl,            arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl,            heterocyclyl, and heterocyclylalkyl;

    -   each L⁴ is independently a fused-tricyclic saturated, partially        unsaturated, or aromatic heterocyclic ring system that is        optionally substituted with one or more groups independently        selected from oxo, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl,        arylalkoxycarbonyl, carboxy, formyl, halo, haloalkyl, hydroxy,        hydroxyalkyl, —NR^(a)R, (NR^(a)R^(b))alkyl,        (NR^(a)R^(b))carbonyl, cyano, nitro, SOR⁴, SO₂R⁴, -alkylSO₂R⁴,        haloalkoxy, cyanoalkyl, NR⁴SO₂R⁴, cycloalkyl, (halo)cycloalkyl,        heterocycle, (cycloalkyl)alkyl, (heterocycle)alkyl, wherein each        alkyl, heterocycle and cycloalkyl is optionally substituted with        one or more halo;        -   each R⁴ is independently selected from H, alkyl, haloalkyl,            aryl, and arylalkyl; and        -   R^(a) and R^(b) are independently selected from the group            consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl, aryl,            arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl,            heterocyclyl, and heterocyclylalkyl;

    -   each L⁵ is independently a —CR═CR-fused bicyclic saturated,        partially unsaturated, or aromatic heterocyclic ring system that        is optionally substituted with one or more groups independently        selected from oxo, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl,        arylalkoxycarbonyl, carboxy, formyl, halo, haloalkyl, hydroxy,        hydroxyalkyl, —NR^(a)R^(b), (NR^(a)R^(b))alkyl,        (NR^(a)R^(b))carbonyl, cyano, nitro, SOR⁴, SO₂R⁴, -alkylSO₂R⁴,        haloalkoxy, cyanoalkyl, NR⁴SO₂R⁴, cycloalkyl, (halo)cycloalkyl,        heterocycle, (cycloalkyl)alkyl, (heterocycle)alkyl, wherein each        alkyl, heterocycle and cycloalkyl is optionally substituted with        one or more halo;        -   each R is independently selected from H or alkyl;        -   each R⁴ is independently selected from H, alkyl, haloalkyl,            aryl, and arylalkyl; and        -   R^(a) and R^(b) are independently selected from the group            consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl, aryl,            arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl,            heterocyclyl, and heterocyclylalkyl;

    -   each L⁶ is independently a —CR═CR-fused-tricyclic saturated,        partially unsaturated, or aromatic heterocyclic ring system that        is optionally substituted with one or more groups independently        selected from oxo, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl,        arylalkoxycarbonyl, carboxy, formyl, halo, haloalkyl, hydroxy,        hydroxyalkyl, —NR^(a)R^(b), (NR^(a)R^(b))alkyl,        (NR^(a)R^(b))carbonyl, cyano, nitro, SOR⁴, SO₂R⁴, -alkylSO₂R⁴,        haloalkoxy, cyanoalkyl, NR⁴SO₂R⁴, cycloalkyl, (halo)cycloalkyl,        heterocycle, (cycloalkyl)alkyl, (heterocycle)alkyl, wherein each        alkyl, heterocycle and cycloalkyl is optionally substituted with        one or more halo;        -   each R is independently selected from H or alkyl;        -   each R⁴ is independently selected from H, alkyl, haloalkyl,            aryl, and arylalkyl; and        -   R^(a) and R^(b) are independently selected from the group            consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl, aryl,            arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl,            heterocyclyl, and heterocyclylalkyl;

    -   each L⁷ is independently:

-   -   -   wherein:            -   each H^(1.1) is independently a fused-bicyclic                saturated, partially unsaturated, or aromatic                heterocyclic ring system that is optionally substituted                with one or more R²            -   each R² is independently selected from halo, —R^(L7),                —OR^(L7), —SR^(L7), —N(R^(L7))₂, —CF₃, —CCl₃, —OCF₃,                —CN, —NO₂, —N(R^(L7))C(═O)R^(L7), —C(═O)R^(L7),                —OC(═O)R^(L7), —C(O)OR^(L7), —C(═O)NR^(L7),                —S(═O)R^(L7), —S(═O)₂OR^(L7), —S(═O)₂R^(L7),                —OS(═O)₂OR^(L7), and —S(═O)₂NR^(L7);            -   each R^(L) is independently —H, alkyl, aryl, arylalkyl,                or heterocycle; and            -   each aa is independently 1, 2, 3, or 4;

    -   each L⁹ is independently a fused-tetracyclic saturated,        partially unsaturated, or aromatic heterocyclic ring system that        is optionally substituted with one or more groups independently        selected from oxo, halo, —R^(L7), —OR^(L7), —SR^(L7), —CF₃,        —CCl₃, —OCF₃, —CN, —NO₂, —N(R^(L7))C(═O)R^(L7), —C(═O)R^(L7),        —OC(═O)R^(L7), —C(O)OR^(L7), —C(═O)NR^(L7), —S(═O)R^(L7),        —S(═O)₂OR^(L7), —S(═O)₂R^(L7), —OS(═O)₂OR^(L7), —S(═O)₂NR^(L7),        alkoxyalkyl, arylalkoxycarbonyl, halo, haloalkyl, hydroxyalkyl,        —NR^(a)R^(b), (NR^(a)R^(b))alkyl, and (NR^(a)R^(b))carbonyl;        -   each R^(L7) is independently —H, alkyl, aryl, arylalkyl, or            heterocycle;        -   R^(a) and R^(b) are each independently selected from the            group consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl,            aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl,            cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl;

    -   each L¹⁰ is independently a fused-pentacyclic saturated,        partially unsaturated, or aromatic heterocyclic ring system that        is optionally substituted with one or more groups independently        selected from oxo, halo, —R^(L7), —OR^(L7), —SR^(L7), —CF₃,        —CCl₃, —OCF₃, —CN, —NO₂, —N(R^(L7))C(═O)R^(L7), —C(═O)R^(L7),        —OC(═O)R^(L7), —C(O)OR^(L7), —C(═O)NR^(L7), —S(═O)R^(L7),        —S(═O)₂OR^(L7), —S(═O)₂R^(L7), —OS(═O)₂OR^(L7), —S(═O)₂NR^(L7),        alkoxyalkyl, arylalkoxycarbonyl, halo, haloalkyl, hydroxyalkyl,        —NR^(a)R^(b), (NR^(a)R^(b))alkyl, and (NR^(a)R^(b))carbonyl;        -   each R^(L) is independently —H, alkyl, aryl, arylalkyl, or            heterocycle;        -   R^(a) and R^(b) are each independently selected from the            group consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl,            aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl,            cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl;

    -   each L¹¹ is independently a six-ring fused saturated, partially        unsaturated, or aromatic heterocyclic ring system that is        optionally substituted with one or more groups independently        selected from oxo, halo, —R^(L7), —OR^(L7), —SR^(L7), —CF₃,        —CCl₃, —OCF₃, —CN, —NO₂, —N(R L⁷)C(═O)R^(L7), —C(═O)R^(L7),        —OC(═O)R^(L7), —C(O)OR^(L7), —C(═O)NR^(L7), —S(═O)R^(L7),        —S(═O)₂OR^(L7), —S(═O)₂R^(L7), —OS(═O)₂OR^(L7), —S(═O)₂NR^(L7),        alkoxyalkyl, arylalkoxycarbonyl, halo, haloalkyl, hydroxyalkyl,        —NR^(a)R^(b), (NR^(a)R^(b))alkyl, and (NR^(a)R^(b))carbonyl;        -   each R^(L7) is independently —H, alkyl, aryl, arylalkyl, or            heterocycle;        -   R^(a) and R^(b) are each independently selected from the            group consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl,            aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl,            cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl;

    -   each R9⁰ is independently selected from alkoxy, alkoxyalkyl,        alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl,        aryl, arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl,        cycloalkyl, (cycloalkyl)alkenyl, (cycloalkyl)alkyl,        cycloalkyloxyalkyl, haloalkyl, heterocyclyl,        heterocyclylalkenyl, heterocyclylalkoxy, heterocyclylalkyl,        heterocyclyloxyalkyl, hydroxyalkyl, —NR^(c)R^(d),        (NR^(c)R^(d))alkenyl, (NR^(c)R^(d))alkyl, and        (NR^(c)R^(d))carbonyl;        -   R^(c) and R^(d) are independently selected from hydrogen,            alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl,            alkyl, alkylcarbonyl, alkylsulfonyl, aryl,            arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl,            arylcarbonyl, aryloxycarbonyl, arylsulfonyl, cycloalkyl,            cycloalkylsulfonyl, formyl, haloalkoxycarbonyl,            heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl,            heterocyclylalkylcarbonyl, heterocyclylcarbonyl,            heterocyclyloxycarbonyl, hydroxyalkylcarbonyl,            (NR^(e)R^(f))alkyl, (NR^(e)R^(f))alkylcarbonyl,            (NR^(e)R^(f))carbonyl, (NR^(e)R^(f))sulfonyl, —C(NCN)OR′,            and —C(NCN)NR^(X)R^(Y), wherein R′ is selected from alkyl            and unsubstituted phenyl, and wherein the alkyl part of the            arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and            the heterocyclylalkylcarbonyl are further optionally            substituted with one —NR^(e)R^(f) group; and wherein the            aryl, the aryl part of the arylalkoxycarbonyl, the            arylalkyl, the arylalkylcarbonyl, the arylcarbonyl, the            aryloxycarbonyl, and the arylsulfonyl, the heterocyclyl, and            the heterocyclyl part of the heterocyclylalkoxycarbonyl, the            heterocyclylalkyl, the heterocyclylalkylcarbonyl, the            heterocyclylcarbonyl, and the heterocyclyloxycarbonyl are            further optionally substituted with one, two, or three            substituents independently selected from alkoxy, alkyl,            cyano, halo, haloalkoxy, haloalkyl, and nitro;        -   R^(X) and R^(Y) are independently selected from hydrogen,            alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl,            unsubstituted arylalkoxycarbonyl, unsubstituted arylalkyl,            unsubstituted cycloalkyl, unsubstituted heterocyclyl, and            (NR^(X)R^(Y))carbonyl, wherein Rx and R^(Y) are            independently selected from hydrogen and alkyl;

    -   each R9¹ is independently —N(R^(9a))—NHC(═O)O—R^(9b), wherein        each R^(9a) is independently arylalkyl, alkyl, alkenyl, alkynyl,        aryl, arylalkyl, arylalkenyl, arylalkoxy, halocycloalkyl,        (cycloalkyl)alkenyl, (cycloalkyl)alkoxy, alkylSO₂alkyl,        cycloalkylalkylSO₂alkyl, cyanoalkyl, haloalkyl, cycloalkylalkyl,        cycloalkyl, alkoxyalkyl, alkoxyalkylcarbonylalkyl,        alkoxycarbonylalkyl, alkylsulfanylalkyl,        aryalkoxyalkylcarbonylalkyl, carboxyalkyl, heterocyclylalkyl,        heterocyclyl, heterocyclylcarbonylalkyl, hydroxyalkyl,        NRRCOalkyl, wherein each R is independently selected from        hydrogen and alkyl;

    -   and wherein arylalkyl the alkyl can be substituted with up to        three aryl groups, and the alkyl part of the arylalkyl is        further optionally substituted with one or two additional groups        independently selected from alkoxy, alkylcarbonyloxy, halo,        haloalkoxy, haloalkyl, heterocyclyl, hydroxy;        -   and the aryl part can be substituted with 1, 2, 3, 4, or 5            substituents independently selected from alkoxy,            alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, a second            aryl group, arylalkoxy, arylalkyl, arylcarbonyl, cyano,            halo, haloalkoxy, haloalkyl, heterocyclyl,            heterocyclylalkyl, heterocyclylcarbonyl, hydroxy,            hydroxyalkyl, nitro, —NR^(X)R^(Y), —(NR^(X)R^(Y))alkyl, oxo,            and —P(O)OR₂, wherein each R is independently selected from            hydrogen and alkyl; and wherein the alkyl part of the            arylalkyl and the heterocyclylalkyl are unsubstituted and            wherein the second aryl group, the aryl part of the            arylalkyl, the aryl part of the arylcarbonyl, the            heterocyclyl, and the heterocyclyl part of the            heterocyclylalkyl and the heterocyclylcarbonyl are further            optionally substituted with one, two, or three substituents            independently selected from alkoxy, alkyl, cyano, halo,            haloalkoxy, haloalkyl, and nitro;        -   and the heterocyclyl can be substituted with 1, 2, 3, 4, or            5 substituents independently selected from alkoxy,            alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl,            arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl,            a second heterocyclyl group, heterocyclylalkyl,            heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro,            —NR^(X)R^(Y), (NR^(X)R^(Y))alkyl, and oxo, wherein the alkyl            part of the arylalkyl and the heterocyclylalkyl are            unsubstituted and wherein the aryl, the aryl part of the            arylalkyl; the aryl part of the arylcarbonyl, the second            heterocyclyl group, and the heterocyclyl part of the            heterocyclylalkyl and the heterocyclylcarbonyl are further            optionally substituted with one, two, or three substituents            independently selected from alkoxy, alkyl, cyano, halo,            haloalkoxy, haloalkyl, and nitro; R^(9b) is independently H,            alkyl, aryl, haloalkyl, or arylalkyl;

    -   each R9² is independently —N(R^(9a))—NHC(═O)NR^(9b) ₂; wherein        each R^(9a) is independently arylalkyl, alkyl, alkenyl, alkynyl,        aryl, arylalkyl, arylalkenyl, arylalkoxy, halocycloalkyl,        (cycloalkyl)alkenyl, (cycloalkyl)alkoxy, alkylSO₂alkyl,        cycloalkylalkylSO₂alkyl, cyanoalkyl, haloalkyl cycloalkylalkyl,        cycloalkyl, alkoxyalkyl, alkoxyalkylcarbonylalkyl,        alkoxycarbonylalkyl, alkylsulfanylalkyl,        aryalkoxyalkylcarbonylalkyl, carboxyalkyl, heterocyclylalkyl,        heterocyclylcarbonylalkyl, hydroxyalkyl, NRRCOalkyl, wherein        each R is independently selected from hydrogen and alkyl;

    -   and where in arylalkyl the alkyl can be substituted with up to        three aryl groups, and the alkyl part of the arylalkyl is        further optionally substituted with one or two additional groups        independently selected from alkoxy, alkylcarbonyloxy, halo,        haloalkoxy, haloalkyl, heterocyclyl, hydroxy;        -   and the aryl part can be substituted with 1, 2, 3, 4, or 5            substituents independently selected from alkoxy,            alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, a second            aryl group, arylalkoxy, arylalkyl, arylcarbonyl, cyano,            halo, haloalkoxy, haloalkyl, heterocyclyl,            heterocyclylalkyl, heterocyclylcarbonyl, hydroxy,            hydroxyalkyl, nitro, —NR^(X)R^(Y), —(NR^(X)R^(Y))alkyl, oxo,            and —P(O)OR₂, wherein each R is independently selected from            hydrogen and alkyl; and wherein the alkyl part of the            arylalkyl and the heterocyclylalkyl are unsubstituted and            wherein the second aryl group, the aryl part of the            arylalkyl, the aryl part of the arylcarbonyl, the            heterocyclyl, and the heterocyclyl part of the            heterocyclylalkyl and the heterocyclylcarbonyl are further            optionally substituted with one, two, or three substituents            independently selected from alkoxy, alkyl, cyano, halo,            haloalkoxy, haloalkyl, and nitro;        -   and the heterocyclyl can be substituted with 1, 2, 3, 4, or            5 substituents independently selected from alkoxy,            alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl,            arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl,            a second heterocyclyl group, heterocyclylalkyl,            heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro,            —NR^(X)R^(Y), (NR^(X)R^(Y))alkyl, and oxo, wherein the alkyl            part of the arylalkyl and the heterocyclylalkyl are            unsubstituted and wherein the aryl, the aryl part of the            arylalkyl; the aryl part of the arylcarbonyl, the second            heterocyclyl group, and the heterocyclyl part of the            heterocyclylalkyl and the heterocyclylcarbonyl are further            optionally substituted with one, two, or three substituents            independently selected from alkoxy, alkyl, cyano, halo,            haloalkoxy, haloalkyl, and nitro; R^(9b) is independently H,            alkyl, aryl, haloalkyl, or arylalkyl;

    -   each R9³ is independently —N(R^(9a))—NHC(═O)R^(9b), wherein each        R^(9a) is independently arylalkyl, alkyl, alkenyl, alkynyl,        aryl, arylalkyl, arylalkenyl, arylalkoxy, halocycloalkyl,        (cycloalkyl)alkenyl, (cycloalkyl)alkoxy, alkylSO₂alkyl,        cycloalkylalkylSO₂alkyl, cyanoalkyl, haloalkyl, cycloalkylalkyl,        cycloalkyl, alkoxyalkyl, alkoxyalkylcarbonylalkyl,        alkoxycarbonylalkyl, alkylsulfanylalkyl,        aryalkoxyalkylcarbonylalkyl, carboxyalkyl, heterocyclylalkyl,        heterocyclyl, heterocyclylcarbonylalkyl, hydroxyalkyl,        NRRCOalkyl, wherein each R is independently selected from        hydrogen and alkyl; and where in arylalkyl the alkyl can be        substituted with up to three aryl groups, and the alkyl part of        the arylalkyl is further optionally substituted with one or two        additional groups independently selected from alkoxy,        alkylcarbonyloxy, halo, haloalkoxy, haloalkyl, heterocyclyl,        hydroxy;        -   and the aryl part can be substituted with 1, 2, 3, 4, or 5            substituents independently selected from alkoxy,            alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, a second            aryl group, arylalkoxy, arylalkyl, arylcarbonyl, cyano,            halo, haloalkoxy, haloalkyl, heterocyclyl,            heterocyclylalkyl, heterocyclylcarbonyl, hydroxy,            hydroxyalkyl, nitro, —NR^(X)R^(Y), —(NR^(X)R^(Y))alkyl, oxo,            and —P(O)OR₂, wherein each R is independently selected from            hydrogen and alkyl; and wherein the alkyl part of the            arylalkyl and the heterocyclylalkyl are unsubstituted and            wherein the second aryl group, the aryl part of the            arylalkyl, the aryl part of the arylcarbonyl, the            heterocyclyl, and the heterocyclyl part of the            heterocyclylalkyl and the heterocyclylcarbonyl are further            optionally substituted with one, two, or three substituents            independently selected from alkoxy, alkyl, cyano, halo,            haloalkoxy, haloalkyl, and nitro;        -   and the heterocyclyl can be substituted with 1, 2, 3, 4, or            5 substituents independently selected from alkoxy,            alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl,            arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl,            a second heterocyclyl group, heterocyclylalkyl,            heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro,            —NR^(X)R^(Y), —(NR^(X)R^(Y))alkyl, and oxo, wherein the            alkyl part of the arylalkyl and the heterocyclylalkyl are            unsubstituted and wherein the aryl, the aryl part of the            arylalkyl; the aryl part of the arylcarbonyl, the second            heterocyclyl group, and the heterocyclyl part of the            heterocyclylalkyl and the heterocyclylcarbonyl are further            optionally substituted with one, two, or three substituents            independently selected from alkoxy, alkyl, cyano, halo,            haloalkoxy, haloalkyl, and nitro; R^(9b) is independently H,            alkyl, aryl, haloalkyl, or arylalkyl;

    -   each A⁰ is independently:

-   -   -   wherein:            -   each R^(A3) is independently selected from alkoxy,                alkoxyalkyl, alkoxycarbonyl, alkyl, arylalkoxycarbonyl,                carboxy, formyl, halo, haloalkyl, hydroxy, hydroxyalkyl,                —NR^(a)R^(b), (NR^(a)R^(b))alkyl, and                (NR^(a)R^(b))carbonyl; R^(a) and R^(b) are each                independently selected from the group consisting of                hydrogen, alkenyl, alkyl, alkylcarbonyl, aryl,                arylalkyl, arylalkylcarbonyl, cycloalkyl,                cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl;                and each            -   bb is independently 0, 1, 2, 3, or 4; or            -   each A⁰ is independently a six-membered heteroaromatic                ring containing one, two, or three nitrogen atoms, which                ring is optionally substituted with 1, 2, 3, or 4 R^(A3)                groups;

    -   each A¹ is independently:

-   -   -   wherein:            -   each R^(A1) is independently selected from cyano, nitro,                SOR⁴, SO₂R⁴, -alkylSO₂R⁴, haloalkoxy, cyanoalkyl,                NR⁴SO₂R⁴, cycloalkyl, (halo)cycloalkyl, heterocycle,                (cycloalkyl)alkyl, (heterocycle)alkyl, wherein each                alkyl, heterocycle and cycloalkyl is optionally                substituted with one or more halo; and            -   each R⁴ is independently selected from H, alkyl,                haloalkyl, aryl, and arylalkyl;            -   each cc is independently 1, 2, 3, or 4

    -   each A² is independently:

-   -   -   wherein:            -   each R^(A1) is independently selected from cyano, nitro,                SOR⁴, SO₂R⁴, -alkylSO₂R⁴, haloalkoxy, cyanoalkyl,                NR⁴SO₂R⁴, cycloalkyl, (halo)cycloalkyl, heterocycle,                (cycloalkyl)alkyl, (heterocycle)alkyl, wherein each                alkyl, heterocycle and cycloalkyl is optionally                substituted with one or more halo;        -   each R^(A3) is independently selected from alkoxy,            alkoxyalkyl, alkoxycarbonyl, alkyl, arylalkoxycarbonyl,            carboxy, formyl, halo, haloalkyl, hydroxy, hydroxyalkyl,            —NR^(a)R^(b), (NR^(a)R^(b))alkyl, and (NR^(a)R^(b))carbonyl;            R^(a) and R^(b) are each independently selected from the            group consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl,            aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl,            cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl;        -   each R⁴ is independently selected from H, alkyl, haloalkyl,            aryl, and arylalkyl;        -   R^(a) and R^(b) are independently selected from the group            consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl, aryl,            arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl,            heterocyclyl, and heterocyclylalkyl;        -   each bb is 0, 1, 2, 3, or 4; each cc is 1, 2, 3, or 4; and            the sum of bb and cc is 1, 2, 3, or 4;

    -   each A³ is independently a six-membered heteroaromatic ring        containing one, two, or three nitrogen atoms, which ring is        substituted with one or more R groups, and which ring is        optionally substituted with one or more R^(A3) groups;

    -   each A⁴ is independently:

-   -   -   wherein:            -   each H⁵ is independently a phenyl ring or a six-membered                heteroaromatic ring, which H⁵ is optionally substituted                with one or more groups independently selected from                R^(A1) and R^(A3); and each X^(A) is independently O,                NR, SO, SO₂, C(═O), NRC(═O), C(═O)NR, CR═CR, NRC(═O)NR,                allenyl, alkynyl, or absent and each R is independently                selected from H or alkyl;

    -   each A⁵ is independently:

-   -   -   wherein:            -   each H⁶ is independently a phenyl ring or a six-membered                heteroaromatic ring, which H⁶ is optionally substituted                with one or more groups independently selected from                R^(A1) and R^(A3); and each X^(A) is independently O,                NR, SO, SO₂, C(═O), NRC(═O), C(═O)NR, CR═CR, NRC(═O)NR,                allenyl, alkynyl, or absent; provided that at least one                X^(A) is present and each R is independently selected                from H or alkyl;

-   -   each A⁶ is independently:        -   wherein:            -   each X^(A) is independently O, NR, SO, SO₂, C(═O),                NRC(═O), C(═O)NR, CR═CR, allenyl, alkynyl, or absent;                provided that at least one X^(A) is present and each R                is independently selected from H or alkyl;    -   each A⁷ is independently:

-   -   -   wherein:            -   each H⁷ is independently a five-membered heteroaromatic                ring, which H⁷ is            -   optionally substituted with one or more groups                independently selected from R^(A1) and R^(A3);            -   and            -   each X^(A) is independently O, NR, SO, SO₂, C(═O),                NRC(═O), C(═O)NR, CR═CR, NRC(═O)NR, allenyl, alkynyl, or                absent; and each R is independently selected from H or                alkyl;

    -   each A⁸ is independently:

-   -   -   wherein:            -   each H⁷ is independently a five-membered heteroaromatic                ring, which H⁷ is optionally substituted with one or                more groups independently selected from R^(A1) and                R^(A3);            -   each H⁸ is independently a phenyl ring, which is                optionally substituted with one or more groups                independently selected from R^(A1) and R^(A3); and            -   each X^(A) is independently O, NR, SO, SO₂, C(═O),                NRC(═O), C(═O)NR, CR═CR, NRC(═O)NR, allenyl, alkynyl, or                absent and each R is independently selected from H or                alkyl;

    -   each A⁹ is independently:

-   -   -   wherein:            -   each H⁷ is independently a five-membered heteroaromatic                ring, which H⁷ is optionally substituted with one or                more groups independently selected from R^(A1) and                R^(A3); and            -   each X^(A) is independently O, NR, SO, SO₂, C(═O),                NRC(═O), C(═O)NR, CR═CR, NRC(═O)NR, allenyl, alkynyl, or                absent and each R is independently selected from H or                alkyl;

    -   each A¹⁰ is independently:

-   -   -   wherein:            -   each H⁸ is independently a phenyl ring, which is                optionally substituted with one or more groups                independently selected from R^(A1) and R^(A3);            -   each H⁹ is independently a six-membered heteroaromatic                ring, which is optionally substituted with one or more                groups independently selected from R^(A1) and R^(A3);                and            -   each X^(A) is independently O, NR, SO, SO₂, C(═O),                NRC(═O), C(═O)NR, CR═CR, NRC(═O)NR, allenyl, alkynyl, or                absent and each R is independently selected from H or                alkyl;

-   -   each A¹¹ is independently:        -   wherein:            -   each X^(A) is independently O, NR, SO, SO₂, C(═O),                NRC(═O), C(═O)NR, CR═CR, NRC(═O)NR, allenyl, alkynyl, or                absent and each R is independently selected from H or                alkyl;            -   each H¹⁰ is independently a 5-15 carbon unsaturated,                partially unsaturated or saturated bicyclic ring system                that is optionally fused to an aryl, which H¹⁰ is                optionally substituted with one or more groups                independently selected from oxo, alkoxy, alkoxyalkyl,                alkoxycarbonyl, alkyl, arylalkoxycarbonyl, carboxy,                formyl, halo, haloalkyl, hydroxy, hydroxyalkyl,                —NR^(a)R^(b), (NR^(a)R^(b))alkyl, and                (NR^(a)R^(b))carbonyl, cyano, nitro, SOR⁴, SO₂R⁴,                -alkylSO₂R⁴, haloalkoxy, cyanoalkyl, NR⁴SO₂R⁴,                cycloalkyl, (halo)cycloalkyl, heterocycle,                (cycloalkyl)alkyl, and (heterocycle)alkyl, wherein each                alkyl, heterocycle and cycloalkyl is optionally                substituted with one or more halo; and            -   each R⁴ is independently selected from H, alkyl,                haloalkyl, aryl, and arylalkyl    -   each A¹² is independently:

-   -   -   wherein:            -   each X^(A) is independently O, NR, SO, SO₂, C(═O),                NRC(═O), C(═O)NR, CR═CR, NRC(═O)NR, allenyl, alkynyl, or                absent and each R is independently selected from H or                alkyl;            -   each H^(1.1) is independently a 5-15 carbon unsaturated,                partially unsaturated or saturated bicyclic ring system                that contains one or more heteroatoms that is optionally                fused to an aryl, which H^(1.1) is optionally                substituted with one or more groups independently                selected from oxo, alkoxy, alkoxyalkyl, alkoxycarbonyl,                alkyl, arylalkoxycarbonyl, carboxy, formyl, halo,                haloalkyl, hydroxy, hydroxyalkyl, —NR^(a)R^(b),                (NR^(a)R^(b))alkyl, and (NR^(a)R^(b))carbonyl, cyano,                nitro, SOR⁴, SO₂R⁴, -alkylSO₂R⁴, haloalkoxy, cyanoalkyl,                NR⁴SO₂R⁴, cycloalkyl, (halo)cycloalkyl, heterocycle,                (cycloalkyl)alkyl, and (heterocycle)alkyl, wherein each                alkyl, heterocycle and cycloalkyl is optionally                substituted with one or more halo; and        -   each R⁴ is independently selected from H, alkyl, haloalkyl,            aryl, and arylalkyl; and

-   -   each A¹³ is independently:        -   wherein:            -   each H¹² is independently a fused aromatic bicyclic                carbocycle, which is optionally substituted with one or                more groups independently selected from R^(A1) and                R^(A3); and            -   each X^(A) is independently O, NR, SO, SO₂, C(═O),                NRC(═O), C(═O)NR, CR═CR, NRC(═O)NR, allenyl, alkynyl, or                absent and each R is independently selected from H or                alkyl;

-   -   each A¹⁴ is independently:        -   wherein:            -   each H¹³ is independently a fused aromatic bicyclic                heterocycle that comprises at least one heteroatom in                the ring system, which ring system is optionally                substituted with one or more groups independently                selected from R^(A1) and R^(A3); and            -   each X^(A) is independently O, NR, SO, SO₂, C(═O),                NRC(═O), C(═O)NR, CR═CR, NRC(═O)NR, allenyl, alkynyl, or                absent and each R is independently selected from H or                alkyl;    -   each A¹⁵ is independently:

-   -   -   wherein:            -   each H¹⁴ is independently a fused unsaturated, partially                unsaturated or saturated tricyclic carbocycle which is                optionally substituted with one or more groups                independently selected from oxo, R^(A1) and R^(A3); and            -   each X^(A) is independently O, NR, SO, SO₂, C(═O),                NRC(═O), C(═O)NR, CR═CR, NRC(═O)NR, allenyl, alkynyl, or                absent and each R is independently selected from H or                alkyl;

-   -   each A¹⁶ is independently:        -   wherein:            -   each H¹⁵ is independently a fused unsaturated, partially                unsaturated or saturated tricyclic heterocycle that                comprises at least one heteroatom in the ring system,                which ring system is optionally substituted with one or                more groups independently selected from R^(A1) and                R^(A3); and            -   each X^(A) is independently O, NR, SO, SO₂, C(═O),                NRC(═O), C(═O)NR, CR═CR, NRC(═O)NR, allenyl, alkynyl, or                absent and each R is independently selected from H or                alkyl;    -   each A¹⁷ is independently:

-   -   -   wherein:            -   each H¹⁶ is independently a fused bicyclic carbocyclic                ring system wherein one ring is aromatic and another                ring is partially or fully saturated, which ring system                is optionally substituted with one or more groups                independently selected from oxo, R^(A1) and R^(A3); and            -   each X^(A) is independently O, NR, SO, SO₂, C(═O),                NRC(═O), C(═O)NR, CR═CR, NRC(═O)NR, allenyl, alkynyl, or                absent and each R is independently selected from H or                alkyl;

    -   each A¹⁸ is independently:

-   -   -   wherein:            -   each H⁷ is independently a fused bicyclic ring system                comprising at least one heteroatom, wherein one ring is                aromatic and another ring is partially or fully                saturated, which ring system is optionally substituted                with one or more groups independently selected from oxo,                R^(A1) and R^(A3); and            -   each X^(A) is independently O, NR, SO, SO₂, C(═O),                NRC(═O), C(═O)NR, CR═CR, NRC(═O)NR, allenyl, alkynyl, or                absent and each R is independently selected from H or                alkyl;

    -   each A²¹ is independently:

-   -   -   wherein:            -   each H⁴⁰ is independently an anti-aromatic monocyclic or                fused carbocyclic ring system, which carbocyclic ring                system is optionally substituted with one or more groups                independently selected from R^(A1) and R^(A3); and            -   each X^(A) is independently O, NR, SO, SO₂, C(═O),                NRC(═O), C(═O)NR, CR═CR, NRC(═O)NR, allenyl, alkynyl, or                absent and each R is independently selected from H or                alkyl;

    -   each W¹ is independently —X^(A)—:        -   wherein:            -   each X^(A) is independently O, NR, SO, SO₂, C(═O),                NRC(═O), C(═O)NR, CR═CR, NRC(═O)NR, allenyl, alkynyl, or                absent and each R is independently selected from H or                alkyl;

-   -   each W² is independently:        -   wherein:            -   each H²⁰ is independently a fused aromatic bicyclic                carbocycle, which is optionally substituted with one or                more groups independently selected from R^(A1) and                R^(A3); and            -   each X^(A) is independently O, NR, SO, SO₂, C(═O),                NRC(═O), C(═O)NR, CR═CR, NRC(═O)NR, allenyl, alkynyl, or                absent and each R is independently selected from H or                alkyl;    -   each W³ is independently:

-   -   -   wherein:            -   each H²¹ is independently a fused bicyclic carbocyclic                ring system wherein one ring is aromatic and another                ring is partially or fully saturated, which ring system                is optionally substituted with one or more groups                independently selected from oxo, R^(A1) and R^(A3); and            -   each X^(A) is independently O, NR, SO, SO₂, C(═O),                NRC(═O), C(═O)NR, CR═CR, NRC(═O)NR, allenyl, alkynyl, or                absent and each R is independently selected from H or                alkyl;

    -   each W⁴ is independently:

-   -   -   wherein:            -   each H²² is independently a fused aromatic bicyclic                heterocycle that comprises at least one heteroatom in                the ring system, which ring system is optionally                substituted with one or more groups independently                selected from R^(A1) and R^(A3); and            -   each X^(A) is independently O, NR, SO, SO₂, C(═O),                NRC(═O), C(═O)NR, CR═CR, NRC(═O)NR, allenyl, alkynyl, or                absent and each R is independently selected from H or                alkyl;

-   -   each W⁵ is independently:        -   wherein:            -   each H²³ is independently a fused bicyclic ring system                comprising at least one heteroatom, wherein one ring is                aromatic and another ring is partially or fully                saturated, which ring system is optionally substituted                with one or more groups independently selected from oxo,                R^(A1) and R^(A3); and            -   each X^(A) is independently O, NR, SO, SO₂, C(═O),                NRC(═O), C(═O)NR, CR═CR, NRC(═O)NR, allenyl, alkynyl, or                absent and each R is independently selected from H or                alkyl;    -   each W⁶ is independently:

-   -   -   wherein:            -   each H²⁴ is independently a fused unsaturated, partially                unsaturated or saturated tricyclic carbocycle, which is                optionally substituted with one or more groups                independently selected from oxo, R^(A1) and R^(A3); and            -   each X^(A) is independently O, NR, SO, SO₂, C(═O),                NRC(═O), C(═O)NR, CR═CR, NRC(═O)NR, allenyl, alkynyl, or                absent and each R is independently selected from H or                alkyl;

-   -   each W⁷ is independently:        -   wherein:            -   each H²⁶ is independently a 5-15 carbon unsaturated,                partially unsaturated or saturated bicyclic ring system                which ring system is optionally substituted with one or                more groups independently selected from oxo, R^(A1) and                R^(A3); and            -   each X^(A) is independently O, NR, SO, SO₂, C(═O),                NRC(═O), C(═O)NR, CR═CR, NRC(═O)NR, allenyl, alkynyl, or                absent and each R is independently selected from H or                alkyl;    -   each W⁸ is independently:

-   -   -   wherein:            -   each H²⁷ is independently a fused unsaturated, partially                unsaturated or saturated tricyclic heterocycle that                comprises at least one heteroatom in the ring system,                which ring system is optionally substituted with one or                more groups independently selected from R^(A1) and                R^(A3); and            -   each X^(A) is independently O, NR, SO, SO₂, C(═O),                NRC(═O), C(═O)NR, CR═CR, NRC(═O)NR, allenyl, alkynyl, or                absent and each R is independently selected from H or                alkyl;

    -   each W⁹ is independently:

-   -   -   wherein:            -   each H²⁹ is independently a 5-15 carbon unsaturated,                partially unsaturated or saturated bicyclic ring system                that contains one or more heteroatoms; and            -   each X^(A) is independently O, NR, SO, SO₂, C(═O),                NRC(═O), C(═O)NR, CR═CR, NRC(═O)NR, allenyl, alkynyl, or                absent and each R is independently selected from H or                alkyl;

    -   each W¹⁰ is independently —H³⁰═C═H³¹—        -   wherein each of —H³⁰ and H³¹ is independently a saturated            6-membered heterocyclic ring comprising one or more            heteroatoms, which ring is optionally substituted with oxo;

    -   each W¹¹ is independently —H³²═C═H³³—        -   wherein each of —H³² and H³³ is independently a saturated            5-membered heterocyclic ring comprising one or more            heteroatoms, which ring is optionally substituted with oxo;

    -   each W¹² is independently an anti-aromatic monocyclic or fused        carbocyclic ring system, which carbocyclic ring system is        optionally substituted with one or more groups independently        selected from R^(A1) and R^(A3);

    -   each W¹³ is independently a phenyl ring that is optionally        substituted with one or more groups independently selected from        R^(A1) and R^(A3);

    -   each W¹⁴ is independently a 5 or 6 membered heteroaryl ring that        is optionally substituted with one or more groups independently        selected from R^(A1) and R^(A3);

    -   each W¹⁵ is independently a fused unsaturated, partially        unsaturated or saturated tetracyclic carbocyclic ring, which        ring system is optionally substituted with one or more groups        independently selected from oxo, R^(A1) and R^(A3);

    -   each W¹⁶ is independently a fused unsaturated, partially        unsaturated or saturated tetracyclic heterocycle that comprises        at least one heteroatom in the ring system, which ring system is        optionally substituted with one or more groups independently        selected from oxo, R^(A1) and R^(A3);

    -   each W⁷ is independently a fused unsaturated, partially        unsaturated or saturated pentacyclic carbocyclic ring system,        which ring system is optionally substituted with one or more        groups independently selected from oxo, R^(A1) and R^(A3);

    -   each W¹⁸ is independently a fused unsaturated, partially        unsaturated or saturated pentacyclic heterocycle that comprises        at least one heteroatom in the ring system, which ring system is        optionally substituted with one or more groups independently        selected from oxo, R^(A1) and R^(A3);

    -   each W¹⁹ is independently a fused unsaturated, partially        unsaturated or saturated hexacyclic carbocyclic ring system,        which ring system is optionally substituted with one or more        groups independently selected from oxo, R^(A1) and R^(A3);

    -   each W²⁰ is independently a fused unsaturated, partially        unsaturated or saturated hexacyclic heterocycle that comprises        at least one heteroatom in the ring system, which ring system is        optionally substituted with one or more groups independently        selected from oxo, R^(A1) and R^(A3);

    -   each M⁰ is independently a five membered heteroaryl group        optionally substituted with one or more alkoxycarbonyl, alkyl,        arylalkoxycarbonyl, carboxy, haloalkyl, (NR^(a)R^(b))carbonyl        and trialkylsilylalkoxyalkyl;

    -   each M¹ is independently selected from —C(═O)NH—,        —C(═O)NH—C(R^(M))₂—, —NHC(═O)—, —C(R^(M))₂NHC(═O)—,        —NHC(═O)NR^(M)—, —NHC(═O)O—; wherein each R^(M) is independently        selected from H and alkyl;

    -   each M² is independently a six-membered heteroaromatic ring,        which is optionally substituted with one or more groups        independently selected from R^(A1) and R^(A3);

    -   each M³ is independently:

-   -   each M⁴ is independently:

-   -   each M⁵ is independently:

wherein the bond designated with

is fused to a ring defined for P;

-   -   each M⁶ is independently a bicyclic bridged ring system        comprising 5-15 atoms wherein at least one of the atoms is a        heteroatom;    -   each M⁷ is independently a pyrid-di-yl;    -   each M⁸ is independently partially saturated or a saturated        five-membered ring that comprises one or more heteroatoms and        that is optionally substituted with one or two oxo;    -   each M⁹ is independently a fused-bicyclic saturated, partially        unsaturated, or aromatic heterocyclic ring system that is        optionally substituted with one or more R^(P11);    -   each M¹⁰ is independently a five membered heteroaryl group        substituted with at least one alkoxy, cycloalkyl, cyano,        alkylsulfonyl, arylsulfonyl, NR^(h)R^(h), (NR^(h)R^(h))sulfonyl,        heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy,        alkoxyalkoxy, haloalkoxyalkyloxy, cycloalkoxyalkoxy,        aryloxyalkoxy, heteroaryloxyalkoxy, heterocyclyloxyalkyloxy,        (NR^(h)R^(h))alkoxy, cyanoalkoxy, cycloalkoxy, heterocyclyl,        alkoxyalkyl, cycloalkoxyalkyl, (NR^(h)R^(h))alkyl, wherein each        R^(h) is independently —H, alkyl, alkoxyamino, aryl, arylalkyl,        heterocycle, heterocyclyloxy, alkenyl, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, and        sulfonylalkyl; and wherein the five membered ring is also        optionally substituted with one or more alkoxycarbonyl, alkyl,        arylalkoxycarbonyl, carboxy, haloalkyl, and        (NR^(a)R^(b))carbonyl;    -   each M¹¹ is independently a fused-tricyclic saturated, partially        unsaturated, or aromatic heterocyclic ring system that is        optionally substituted with one or more oxo, halo, —R^(M7),        —OR^(M7), —SR^(M7), —N(R^(M7))₂, —CF₃, —CCl₃, —OCF₃, —CN, —NO₂,        —N(R^(M7))C(═O)R^(M7), —C(═O)R^(M7), —OC(═O)R^(M7),        —C(O)OR^(M7), —C(═O)NR^(M7), —S(═O)R^(M7), —S(═O)₂OR^(M7),        —S(═O)₂R^(M7), —OS(═O)₂OR^(M7), or —S(═O)₂NR^(M7); each R^(M7)        is independently —H, alkyl, aryl, arylalkyl, or heterocycle;    -   each M¹² is independently a fused-pentacyclic, hexacyclic, or        heptacyclic partially unsaturated, or aromatic heterocyclic ring        system that is optionally substituted with one or more oxo halo,        —R^(M7), —OR^(M7), —SR^(M7), —N(R^(M7))₂, —CF₃, —CCl₃, —OCF₃,        —CN, —NO₂, —N(R^(M7))C(═O)R^(M7), —C(═O)R^(M7), —OC(═O)R^(M7),        —C(O)OR^(M7), —C(═O)NR^(M7), —S(═O)R^(M7), —S(═O)₂OR^(M7),        —S(═O)₂R^(M7), —OS(═O)₂OR^(M7), or —S(═O)₂NR^(M7);    -   each R^(M7) is independently —H, alkyl, aryl, arylalkyl, or        heterocycle;    -   each P⁰ is independently:

-   -   -   wherein:            -   X is selected from O, S, S(O), SO₂, CH₂, CHR^(P10), and                C(R^(P10))₂; provided that when pn or pm is 0, X is                selected from CH₂, CHR^(P10), and C(R^(P10))₂;            -   each R^(P10) is independently selected from alkoxy,                alkyl, aryl, halo, haloalkyl, hydroxy, and                —NR^(Pa)R^(Pb), wherein the alkyl can optionally form a                fused three- to six-membered ring with an adjacent                carbon atom, wherein the three- to six-membered ring is                optionally substituted with one or two alkyl groups;            -   each R^(P5) and R^(P6) is independently selected from                alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and                —NR^(Pa)R^(Pb), wherein the alkyl can optionally form a                fused three- to six-membered ring with an adjacent                carbon atom, wherein the three- to six-membered ring is                optionally substituted with one or two alkyl groups;                R^(Pa) and R^(Pb) are each independently H, alkyl, aryl,                or arylalkyl; or R^(Pa) and R^(Pb) taken together with                the atom to which they are attached form a heterocycle;            -   pq and ps are independently 0, 1, 2, 3, or 4;            -   pm and pn are independently 0, 1, or 2;            -   po and pp are independently 1, 2, or 3;            -   R^(P7) and R^(P8) are each independently selected from                hydrogen, alkenyl, alkoxyalkyl, alkyl, haloalkyl, and                (NR^(Pa)R^(Pb))alkyl; or R^(P7) and R^(P8), together                with the carbon atom to which they are attached, form a                five or six membered saturated ring optionally                containing one or two heteroatoms selected from NR^(PZ),                0, and S; wherein R^(PZ) is selected from hydrogen and                alkyl;            -   R^(P9) is selected from hydrogen and alkyl;

    -   each P¹ is independently:

-   -   -   wherein:            -   X is selected from O, S, S(O), SO₂, CH₂, CHR^(P10), and                C(R^(P10))₂; provided that when pn is 0, X is selected                from CH₂, CHR^(P10), and C(R^(P10))₂;            -   each R^(P10) is independently selected from alkoxy,                alkyl, aryl, halo, haloalkyl, hydroxy, and                —NR^(Pa)R^(Pb), wherein the alkyl can optionally form a                fused three- to six-membered ring with an adjacent                carbon atom, wherein the three- to six-membered ring is                optionally substituted with one or two alkyl groups;            -   at least one R^(P11) is independently selected from                cyano, alkylsulfonyl, arylsulfonyl,                (NR^(h)R^(h))sulfonyl, heterocyclylsulfonyl,                heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy,                haloalkoxyalkyloxy, cycloalkyoxyalkyloxy,                aryloxyalkyloxy, heteroaryloxyakyloxy,                heterocyclooxyalkyloxy, (NR^(h)R^(h)a)lkyloxy,                cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo,                heterocyclyl, —NR^(hh)R^(h), (NR^(hh)R^(h))alkyl,                (NR^(hh)R^(h))carbonyl, wherein each R^(h) is                independently —H, alkyl, alkoxyamino, aryl, arylalkyl,                heterocycle, heterocyclyoxy, alkenyl, alkenyloxy,                alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl,                haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,                dialkylaminoalkyl, sulfonylalkyl; and when two R^(h)                groups are present then they may come together with the                atoms to which they are bound to form a 4-15 membered                heterocyclic ring; wherein each R^(hh) is independently                aryl, arylalkyl, heterocycle, heterocyclyoxy,                alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl,                haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,                dialkylaminoalkyl, sulfonylalkyl, (NR^(h)R^(h))sulfonyl,                heteroarylsulfonyl, —S(═O)₂R^(h), —C(═O)R^(h),                —C(═O)NR^(h)R^(h); and the remaining R^(P11) are                independently selected from R^(P5), cyano,                alkylsulfonyl, arylsulfonyl, (NR^(h)R^(h))sulfonyl,                heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy,                alkoxyalkyloxy, haloalkoxyalkyloxy,                cycloalkyoxyalkyloxy, aryloxyalkyloxy,                heteroaryloxyakyloxy, heterocyclooxyalkyloxy,                (NR^(h)R^(h))alkyloxy, cyanoalkoxy, cyanocycloalkyloxy,                cycloalkyloxy, oxo, heterocyclyl; wherein each R^(h) is                independently —H, alkyl, alkoxyamino, aryl, arylalkyl,                heterocycle, heterocyclyoxy, alkenyl, alkenyloxy,                alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl,                haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,                dialkylaminoalkyl, sulfonylalkyl; and when two R^(h)                groups are present then they may come together with the                atoms to which they are bound to form a 4-15 membered                heterocyclic ring;            -   ps is 1, 2, 3, or 4;            -   pn is 0, 1, or 2;

    -   each P² is independently:

-   -   -   wherein:            -   each R^(P12) is independently selected from R^(P5),                R^(P11), —C(═O)OR^(h), cyano, alkylsulfonyl,                arylsulfonyl, (NR^(h)R^(h))sulfonyl,                heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy,                alkoxyalkyloxy, haloalkoxyalkyloxy,                cycloalkyoxyalkyloxy, aryloxyalkyloxy,                heteroaryloxyakyloxy, heterocyclooxyalkyloxy,                (NR^(h)R^(h))alkyloxy, cyanoalkoxy, cyanocycloalkyloxy,                cycloalkyloxy, oxo, heterocyclyl; wherein each R^(h) is                independently —H, alkyl, alkoxyamino, aryl, arylalkyl,                heterocycle, heterocyclyoxy, alkenyl, alkenyloxy,                alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl,                haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,                dialkylaminoalkyl, sulfonylalkyl; and when two R^(h)                groups are present then they may come together with the                atoms to which they are bound to form a 4-15 membered                heterocyclic ring;            -   ps is 1,2,3, or 4;            -   pn is 0, 1, or 2;

    -   each P³ is independently a ring of the formula:

-   -   -   wherein:            -   the ring is substituted with one or more oxo group;            -   each R^(P13) is independently selected from R^(P5),                cyano, alkylsulfonyl, arylsulfonyl,                (NR^(h)R^(h))sulfonyl, heterocyclylsulfonyl,                heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy,                haloalkoxyalkyloxy, cycloalkyoxyalkyloxy,                aryloxyalkyloxy, heteroaryloxyakyloxy,                heterocyclooxyalkyloxy, (NR^(h)R^(h))alkyloxy,                cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo,                heterocyclyl; wherein each R^(h) is independently —H,                alkyl, alkoxyamino, aryl, arylalkyl, heterocycle,                heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,                alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl,                aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,                sulfonylalkyl; and when two R^(h) groups are present                then they may come together with the atoms to which they                are bound to form a 4-15 membered heterocyclic ring;            -   ps is 0, 1, 2, 3, or 4;            -   pn is 0, 1, or 2;

    -   each P⁴ is independently a ring of the formula:

-   -   -   wherein:            -   the ring is optionally substituted with one or more                groups R^(P14) that are independently selected from                alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and                —NR^(Pa)R^(Pb), wherein the alkyl can optionally form a                fused three- to six-membered ring with an adjacent                carbon atom, wherein the three- to six-membered ring is                optionally substituted with one or two alkyl groups; and                where two groups R^(P14) that are attached to the same                carbon when taken together with the carbon to which they                are attached can form a 3-6 membered carbocyclic or                heterocyclic ring;            -   pn is 0, 1, or 2;            -   each R^(f) is independently —H, alkyl, alkoxyamino,                aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl,                alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl,                haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,                dialkylaminoalkyl, sulfonylalkyl, —S(═O)₂NR^(h)R^(h),                —S(═O)₂R^(h), C(═O)R^(h), C(═O)OR^(h),                —C(═O)NR^(h)R^(h); each R^(h) is independently —H,                alkyl, alkoxyamino, aryl, arylalkyl, heterocycle,                heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,                alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl,                aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,                sulfonylalkyl; or when two R^(h) groups are present then                they may come together with the atoms to which they are                bound to form a 4-15 membered heterocyclic ring;

    -   each P⁵ is independently a ring of the formula:

-   -   -   wherein:            -   the ring is optionally substituted with one or more                groups R^(P15) that are independently selected from                alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and                —NR^(Pa)R^(Pb), wherein the alkyl can optionally form a                fused three- to six-membered ring with an adjacent                carbon atom, wherein the three- to six-membered ring is                optionally substituted with one or two alkyl groups; and                where two groups R^(P10) that are attached to the same                carbon when taken together with the carbon to which they                are attached can form a 3-6 membered carbocyclic or                heterocyclic ring;            -   pn is 0, 1, or 2;            -   Z is O, S, S(═O), S(═O)₂, or NR^(f);            -   each R^(f) is independently —H, alkyl, alkoxyamino,                aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl,                alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl,                haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,                dialkylaminoalkyl, sulfonylalkyl, —S(═O)₂NR^(h)R^(h),                —S(═O)₂R^(h), C(═O)R^(h), C(═O)OR^(h),                —C(═O)NR^(h)R^(h); each R^(h) is independently —H,                alkyl, alkoxyamino, aryl, arylalkyl, heterocycle,                heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,                alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl,                aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,                sulfonylalkyl; or when two R^(h) groups are present then                they may come together with the atoms to which they are                bound to form a 4-15 membered heterocyclic ring;

    -   each P⁶ is independently a ring of the formula:

-   -   -   wherein:            -   the ring is substituted with one or more oxo and is                optionally substituted with one or more groups R^(P16)                that are independently selected from alkoxy, alkyl,                aryl, halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb),                wherein the alkyl can optionally form a fused three- to                six-membered ring with an adjacent carbon atom, wherein                the three- to six-membered ring is optionally                substituted with one or two alkyl groups;            -   Z is O, S, S(═O), S(═O)₂, or NR^(f);            -   pn is 0, 1, or 2;                -   each R^(f) is independently —H, alkyl, alkoxyamino,                    aryl, arylalkyl, heterocycle, heterocyclyoxy,                    alkenyl, alkenyloxy, alkynyl, alkoxyalkyl,                    haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,                    alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,                    —S(═O)₂NR^(h)R^(h), —S(═O)₂R^(h), C(═O)R^(h),                    C(═O)OR^(h), —C(═O)NR^(h)R^(h); each R^(h) is                    independently —H, alkyl, alkoxyamino, aryl,                    arylalkyl, heterocycle, heterocyclyoxy, alkenyl,                    alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl,                    cyanoalkyl, haloalkoxyalkyl, aminoalkyl,                    alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl;                    or when two R^(h) groups are present then they may                    come together with the atoms to which they are bound                    to form a 4-15 membered heterocyclic ring;

    -   each P⁷ is a bridged 5-15 membered bicyclic heterocyclic ring        that is attached to the remainder of the compound of formula II        through one N-link and through one C-link; wherein the ring is        optionally substituted with one or more groups independently        selected from R^(P6) and R^(P11);

    -   each P⁸ is independently a ring of the formula:

-   -   -   wherein:            -   ps is 2, 3, 4, 5, or 6;            -   pn is 0, 1 or 2;            -   each R^(P13) is independently selected from alkoxy,                alkyl, aryl, halo, haloalkyl, hydroxy, and                —NR^(Pa)R^(Pb), wherein the alkyl can optionally form a                fused three- to six-membered ring with an adjacent                carbon atom, wherein the three- to six-membered ring is                optionally substituted with one or two alkyl groups;                where in at least one case two groups R^(P13) that are                attached to the same carbon are taken together with the                carbon to which they are attached and form a 4-6                membered heterocyclic ring;

    -   each P¹⁰ is independently:

-   -   -   wherein:            -   X is selected from O, S, S(O), SO₂, CH₂, CHR^(P10), and                C(R^(P10))₂; provided that when pn or pm is 0, X is                selected from CH₂, CHR^(P10), and C(R^(P10))₂;            -   each R^(P10) is independently selected from alkoxy,                alkyl, aryl, halo, haloalkyl, hydroxy, and                —NR^(Pa)R^(Pb), wherein the alkyl can optionally form a                fused three- to six-membered ring with an adjacent                carbon atom, wherein the three- to six-membered ring is                optionally substituted with one or two alkyl groups;            -   each R^(P5) and R^(P6) is independently selected from                alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and                —NR^(Pa)R^(Pb), wherein the alkyl can optionally form a                fused three- to six-membered ring with an adjacent                carbon atom, wherein the three- to six-membered ring is                optionally substituted with one or two alkyl groups;            -   pq and ps are independently 0, 1, 2, 3, or 4;            -   pm and pn are independently 0, 1, or 2;            -   po and pp are independently 1, 2, or 3;

    -   each P¹¹ is independently:

-   -   -   wherein:            -   X is selected from O, S, S(O), SO₂, CH₂, CHR^(P10), and                C(R^(P10))₂; provided that when pn or pm is 0, X is                selected from CH₂, CHR^(P10), and C(R^(P10))₂;            -   each R^(P10) is independently selected from alkoxy,                alkyl, aryl, halo, haloalkyl, hydroxy, and                —NR^(Pa)R^(Pb), wherein the alkyl can optionally form a                fused three- to six-membered ring with an adjacent                carbon atom, wherein the three- to six-membered ring is                optionally substituted with one or two alkyl groups;            -   each R^(P5) and R^(P6) is independently selected from                alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and                —NR^(Pa)R^(Pb), wherein the alkyl can optionally form a                fused three- to six-membered ring with an adjacent                carbon atom, wherein the three- to six-membered ring is                optionally substituted with one or two alkyl groups;            -   pq and ps are independently 0, 1, 2, 3, or 4;            -   pm and pn are independently 0, 1, or 2;            -   po and pp are independently 1, 2, or 3;            -   each P¹² is independently:

-   -   -   wherein:            -   each R^(P6) is independently selected from alkoxy,                alkyl, aryl, halo, haloalkyl, hydroxy, and                —NR^(Pa)R^(Pb), wherein the alkyl can optionally form a                fused three- to six-membered ring with an adjacent                carbon atom, wherein the three- to six-membered ring is                optionally substituted with one or two alkyl groups;            -   pq is independently 0, 1, 2, 3, or 4;            -   pm is independently 0, 1, or 2;            -   pp is independently 1, 2, or 3;            -   ps is 1, 2, 3, or 4;

R^(P11) is independently selected from cyano, alkylsulfonyl,arylsulfonyl, (NR^(h)R^(h))sulfonyl, heterocyclylsulfonyl,heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy,cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy,heterocyclooxyalkyloxy, (NR^(h)R^(h))alkyloxy, cyanoalkoxy,cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl, —NR^(hh)R^(h),(NR^(hh)R^(h))alkyl, (NR^(h)R^(h))carbonyl, wherein each R^(h) isindependently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle,heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl,cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, sulfonylalkyl; and when two R^(h) groups are presentthen they may come together with the atoms to which they are bound toform a 4-15 membered heterocyclic ring; wherein each R^(hh) isindependently aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyloxy,alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,(NR^(h)R^(h))sulfonyl, heteroarylsulfonyl, —S(═O)₂R^(h), —C(═O)R^(h),—C(═O)NR^(h)R^(h); and the remaining R^(P11) are independently selectedfrom R^(P5), cyano, alkylsulfonyl, arylsulfonyl, (NR^(h)R^(h))sulfonyl,heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy,haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy,heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NR^(h)R^(h))alkyloxy,cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl;wherein each R^(h) is independently —H, alkyl, alkoxyamino, aryl,arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two R^(h)groups are present then they may come together with the atoms to whichthey are bound to form a 4-15 membered heterocyclic ring;

-   -   each P¹³ is independently:

-   -   -   wherein:            -   X is selected from O, S, S(O), SO₂, or NR^(h);            -   each R^(P6) is independently selected from alkoxy,                alkyl, aryl, halo, haloalkyl, hydroxy, and                —NR^(Pa)R^(Pb), wherein the alkyl can optionally form a                fused three- to six-membered ring with an adjacent                carbon atom, wherein the three- to six-membered ring is                optionally substituted with one or two alkyl groups;            -   pq is independently 0, 1, 2, 3, or 4;            -   pm and pn are independently 0, 1, or 2 but the sum of pn                and pm is greater than zero;            -   pp are independently 1, 2, or 3;            -   ps is 1, 2, 3, or 4;        -   each R^(P11) is independently selected from cyano,            alkylsulfonyl, arylsulfonyl, (NR^(h)R^(h))sulfonyl,            heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy,            alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy,            aryloxyalkyloxy, heteroaryloxyakyloxy,            heterocyclooxyalkyloxy, (NR^(h)R^(h))alkyloxy, cyanoalkoxy,            cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl,            —NR^(hh)R^(h), (NR^(h)R^(h))alkyl, (NR^(h)R^(h))carbonyl,            wherein each R^(h) is independently —H, alkyl, alkoxyamino,            aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl,            alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl,            haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,            dialkylaminoalkyl, sulfonylalkyl; and when two R^(h) groups            are present then they may come together with the atoms to            which they are bound to form a 4-15 membered heterocyclic            ring; wherein each R^(hh) is independently aryl, arylalkyl,            heterocycle, heterocyclyoxy, alkenyloxy, alkynyl,            alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl,            aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,            sulfonylalkyl, (NR^(h)R^(h))sulfonyl, heteroarylsulfonyl,            —S(═O)₂R^(h), —C(═O)R^(h), —C(═O)NR^(h)R^(h), R^(P5), cyano,            alkylsulfonyl, arylsulfonyl, (NR^(h)R^(h))sulfonyl,            heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy,            alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy,            aryloxyalkyloxy, heteroaryloxyakyloxy,            heterocyclooxyalkyloxy, (NR^(h)R^(h))alkyloxy, cyanoalkoxy,            cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl;            wherein each R^(h) is independently —H, alkyl, alkoxyamino,            aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl,            alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl,            haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,            dialkylaminoalkyl, sulfonylalkyl; and when two R^(h) groups            are present then they may come together with the atoms to            which they are bound to form a 4-15 membered heterocyclic            ring;

    -   each P¹⁴ is independently:

-   -   -   wherein:        -   the ring is substituted with one or more oxo group;            -   X is NR^(f);            -   each R^(f) is independently —H, alkyl, alkoxyamino,                aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl,                alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl,                haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,                dialkylaminoalkyl, sulfonylalkyl, —S(═O)₂NR^(h)R^(h),                —S(═O)₂R^(h), C(═O)R^(h), C(═O)OR^(h),                —C(═O)NR^(h)R^(h); each R^(h) is independently —H,                alkyl, alkoxyamino, aryl, arylalkyl, heterocycle,                heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,                alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl,                aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,                sulfonylalkyl; or when two R^(h) groups are present then                they may come together with the atoms to which they are                bound to form a 4-15 membered heterocyclic ring;            -   each R^(P6) is independently selected from alkoxy,                alkyl, aryl, halo, haloalkyl, hydroxy, and                —NR^(Pa)R^(Pb), wherein the alkyl can optionally form a                fused three- to six-membered ring with an adjacent                carbon atom, wherein the three- to six-membered ring is                optionally substituted with one or two alkyl groups;            -   pq is independently 0, 1, 2, 3, or 4;            -   pm is independently 0, 1, or 2;            -   ps is 1, 2, 3, or 4;            -   R^(P11) is independently selected from cyano,                alkylsulfonyl, arylsulfonyl, (NR^(h)R^(h))sulfonyl,                heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy,                alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy                aryloxyalkyloxy, heteroaryloxyakyloxy,                heterocyclooxyalkyloxy, (NR^(h)R^(h))alkyloxy,                cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo,                heterocyclyl; wherein each R^(h) is independently —H,                alkyl, alkoxyamino, aryl, arylalkyl, heterocycle,                heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,                alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl,                aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, or                sulfonylalkyl; and when two R^(h) groups are present                then they may come together with the atoms to which they                are bound to form a 4-15 membered heterocyclic ring;        -   each P¹⁵ is:

-   -   which is substituted with one or two groups independently        selected from alkoxyalkyl, haloalkoxyalkyl, alkylsulfanyl,        alkylsulfanylalkyl, cyanoalkyl, and cycloalkylalkyl.        -   each P¹⁶ is:

-   -   which is substituted with methylene;        -   each P¹⁷ is:

-   -   which is substituted with one or two groups independently        selected from alkenyl, alkynyl, cycloalkyl, cycloalkylalkenyl,        and cycloalkylalkynyl.        -   each P¹⁸ is:

-   -   which is optionally substituted with one or two groups        independently selected from halo, alkyl, alkoxyalkyl, haloalkyl,        cycloalkyl, and cycloalkylalkyl;        -   each P¹⁹ is:

-   -   wherein each R^(P19a) is independently selected from H and halo;        and each R^(P19b) is independently selected from halo;    -   each —Z⁰— is —C(═O)— or —C(═S)—;    -   each —Z¹— is independently a bond, or —C(R^(Z1))₂—; wherein each        R^(Z1) is independently H, alkyl, haloalkyl, or halo;    -   each —Z²— is independently saturated or partially unsaturated        (C₃-C₈)cycloalkyl that is optionally substituted with one or        more groups independently selected from R^(A1) and R^(A3);    -   each —Z³— is independently saturated, partially unsaturated, or        aromatic 4-8 membered heterocyclic or heteroaryl ring that is        optionally substituted with one or more groups independently        selected from R^(A1) and R^(A3);    -   each —Z⁴— is independently:

-   -   wherein each R⁴ is independently H, alkyl, cyano, aryl, or        heteroaryl;    -   each —Z⁵— is independently:

-   -   wherein each R^(Z5) is independently H, alkyl, cyano, aryl, or        heteroaryl; or two R^(Z5)s together with the nitrogen to which        they are attached form a 4-8 membered heterocyclic ring that is        optionally substituted with one or more oxo and with one or more        groups independently selected from R^(A1) and R^(A3);    -   each —Z⁶— is independently —C(R^(Z1))— and is double bonded to a        carbocyclic P; wherein R^(Z1) is independently H, alkyl,        haloalkyl, or halo;    -   each E⁰ is independently —NR^(Ec)R^(Ed) wherein        -   R^(Ec) and R^(Ed) are each independently selected from            hydrogen, alkenyloxycarbonyl, alkoxyalkylcarbonyl,            alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfonyl, aryl,            arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl,            arylcarbonyl, aryloxycarbonyl, arylsulfonyl, cycloalkyl,            cycloalkylsulfonyl, formyl, haloalkoxycarbonyl,            heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl,            heterocyclylalkylcarbonyl, heterocyclylcarbonyl,            heterocyclyloxycarbonyl, hydroxyalkylcarbonyl,            (NR^(e)R^(f))alkyl, (NR^(e)R^(f))alkylcarbonyl,            (NR^(e)R^(f))carbonyl, (NR^(e)R^(f))sulfonyl, —C(NCN)OR′,            and —C(NCN)NR^(X)R^(Y), wherein R′ is selected from alkyl            and unsubstituted phenyl, and wherein the alkyl part of the            arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and            the heterocyclylalkylcarbonyl are further optionally            substituted with one —NR^(e)R^(f) group; and wherein the            aryl, the aryl part of the arylalkoxycarbonyl, the            arylalkyl, the arylalkylcarbonyl, the arylcarbonyl, the            aryloxycarbonyl, and the arylsulfonyl, the heterocyclyl, and            the heterocyclyl part of the heterocyclylalkoxycarbonyl, the            heterocyclylalkyl, the heterocyclylalkylcarbonyl, the            heterocyclylcarbonyl, and the heterocyclyloxycarbonyl are            further optionally substituted with one, two, or three            substituents independently selected from alkoxy, alkyl,            cyano, halo, haloalkoxy, haloalkyl, and nitro;        -   each E is independently —OC(═O)NR^(Ee)R^(Ef) wherein each            R^(Ee) and R^(Ef) are each independently selected from            hydrogen, alkenyloxycarbonyl, alkoxyalkylcarbonyl,            alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfonyl, aryl,            arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl,            arylcarbonyl, aryloxycarbonyl, arylsulfonyl, cycloalkyl,            cycloalkylsulfonyl, formyl, haloalkoxycarbonyl,            heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl,            heterocyclylalkylcarbonyl, heterocyclylcarbonyl,            heterocyclyloxycarbonyl, hydroxyalkylcarbonyl,            (NR^(e)R^(f))alkyl, (NR^(e)R^(f))alkylcarbonyl,            (NR^(e)R^(f))carbonyl, (NR^(e)R^(f))sulfonyl, —C(NCN)OR′,            and —C(NCN)NR^(X)R^(Y), wherein R′ is selected from alkyl            and unsubstituted phenyl, and wherein the alkyl part of the            arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and            the heterocyclylalkylcarbonyl are further optionally            substituted with one —NR^(e)R^(f) group; and wherein the            aryl, the aryl part of the arylalkoxycarbonyl, the            arylalkyl, the arylalkylcarbonyl, the arylcarbonyl, the            aryloxycarbonyl, and the arylsulfonyl, the heterocyclyl, and            the heterocyclyl part of the heterocyclylalkoxycarbonyl, the            heterocyclylalkyl, the heterocyclylalkylcarbonyl, the            heterocyclylcarbonyl, and the heterocyclyloxycarbonyl are            further optionally substituted with one, two, or three            substituents independently selected from alkoxy, alkyl,            cyano, halo, haloalkoxy, haloalkyl, and nitro; or wherein            R^(Ee) and R^(Ef), together with the nitrogen atom to which            they are attached, form a heterocycle;    -   each E2 is independently —NR^(a)R^(b), wherein R^(a) is        haloalkyl and R^(b) is H, alkyl, alkoxycarbonyl. or haloalkyl;    -   each E3 is independently —NR^(Ec)R^(E3a), wherein R^(E3a) is        (C₃-C₆)cycloalkyloxycarbonyl;    -   each E4 is independently —OC(═O)OR^(E4a), wherein R^(E4a) is        cycloalkyl, aryl, or alkyl;    -   each E5 is independently —NR^(Ec)S(═O)₂OR^(E5a), wherein R^(E5a)        is cycloalkyl, aryl or alkyl;    -   each E6 is independently —NR^(Ec)S(═O)₂R^(E6a), wherein R^(E6a)        is cycloalkyl, aryl, or alkyl;    -   each E⁷ is independently —NR^(Ec)OR^(E7a), wherein R^(E7a) is        cycloalkyl, aryl, alkyl, haloalkyl, cycloalkylalkyl or        heteroaryl;    -   each V⁰ is independently H, alkyl, arylalkyl, alkenyl, CO,        cycloalkylalkyl, cycloalkyl, alkoxyalkyl,        alkoxyalkylcarbonylalkyl, alkoxycarbonylalkyl,        alkylsulfanylalkyl, aryalkoxyalkylcarbonylalkyl, carboxyalkyl,        heterocyclylalkyl, heterocyclylcarbonylalkyl, hydroxyalkyl,        NRRCOalkyl, wherein each R is independently selected from        hydrogen and alkyl;    -   and where in arylalkyl the alkyl can be substituted with up to        three aryl groups, and the alkyl part of the arylalkyl is        further optionally substituted with one or two additional groups        independently selected from alkoxy, alkyocarbonyloxy, halo,        haloalkoxy, haloalkyl, heterocyclyl, hydroxy;    -   and the aryl part can be substituted with 1, 2, 3, 4, or 5        substituents independently selected from alkoxy, alkoxyalkyl,        alkoxycarbonyl, alkyl, alkylcarbonyl, a second aryl group,        arylalkoxy, arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy,        haloalkyl, heterocyclyl, heterocyclylalkyl,        heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro,        —NR^(X)R^(Y), —(NR^(X)R^(Y))alkyl, oxo, and —P(O)OR₂, wherein        each R is independently selected from hydrogen and alkyl; and        wherein the alkyl part of the arylalkyl and the        heterocyclylalkyl are unsubstituted and wherein the second aryl        group, the aryl part of the arylalkyl, the aryl part of the        arylcarbonyl, the heterocyclyl, and the heterocyclyl part of the        heterocyclylalkyl and the heterocyclylcarbonyl are further        optionally substituted with one, two, or three substituents        independently selected from alkoxy, alkyl, cyano, halo,        haloalkoxy, haloalkyl, and nitro;    -   and the heterocyclyl can be substituted with 1, 2, 3, 4, or 5        substituents independently selected from alkoxy, alkoxyalkyl,        alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, arylalkyl,        arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl, a second        heterocyclyl group, heterocyclylalkyl, heterocyclylcarbonyl,        hydroxy, hydroxyalkyl, nitro, —NR^(X)R^(Y), (NR^(X)R^(Y))alkyl,        and oxo, wherein the alkyl part of the arylalkyl and the        heterocyclylalkyl are unsubstituted and wherein the aryl, the        aryl part of the arylalkyl; the aryl part of the arylcarbonyl,        the second heterocyclyl group, and the heterocyclyl part of the        heterocyclylalkyl and the heterocyclylcarbonyl are further        optionally substituted with one, two, or three substituents        independently selected from alkoxy, alkyl, cyano, halo,        haloalkoxy, haloalkyl, and nitro;    -   each V¹ is independently cyanoalkyl, which is optionally        substituted with one or more groups independently selected from        cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle,        heteroaryl, hydroxy, and NR^(Va)R^(Vb)C(═O)O—; R^(Va) and R^(Vb)        are each independently selected from hydrogen, alkenyl, and        alkyl;    -   each V² is independently haloalkyl, which is optionally        substituted with one or more groups independently selected from        cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle,        heteroaryl, hydroxy, and NR^(Va)R^(Vb)C(═O)O—; R^(Va) and R^(Vb)        are each independently selected from hydrogen, alkenyl, and        alkyl;    -   each V³ is independently alkyl, which is substituted with one or        more oxo, and which is optionally substituted with one or more        groups independently selected from cycloalkyl, halo, aryl,        alkenyl, and cyano;    -   each V⁴ is independently haloalkoxyalkyl, which is optionally        substituted with one or more groups independently selected from        cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle,        heteroaryl, hydroxy, and NR^(Va)R^(Vb)C(═O)O—; wherein R^(Va)        and R^(Vb) are each independently selected from hydrogen,        alkenyl, and alkyl;    -   each V⁵ is independently alkylsulfonylalkyl, which is optionally        substituted with one or more groups independently selected from        cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle,        heteroaryl, hydroxy, and NR^(Va)R^(Vb)C(═O)O—; R^(Va) and R^(Vb)        are each independently selected from hydrogen, alkenyl, and        alkyl;    -   each V⁶ is independently arylsulfonylalkyl, which is optionally        substituted with one or more groups independently selected from        cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle,        heteroaryl, hydroxy, and NR^(Va)R^(Vb)C(═O)O—; R^(Va) and R^(Vb)        are each independently selected from hydrogen, alkenyl, and        alkyl;    -   each V⁷ is independently heterocyclosulfonylalkyl, which is        optionally substituted with one or more groups independently        selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl,        heterocycle, heteroaryl, hydroxy, and NR^(Va)R^(Vb)C(═O)O—;        R^(Va) and R^(Vb) are each independently selected from hydrogen,        alkenyl, and alkyl;    -   each V⁸ is independently spirocycloalkyl, which is optionally        substituted with one or more groups independently selected from        cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle,        heteroaryl, hydroxy, and NR^(Va)R^(Vb)C(═O)O—; R^(Va) and R^(Vb)        are each independently selected from hydrogen, alkenyl, and        alkyl;    -   each V⁹ is independently spirocycloalkylalkyl, which is        optionally substituted with one or more groups independently        selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl,        heterocycle, heteroaryl, hydroxy, and NR^(Va)R^(Vb)C(═O)O—;        R^(Va) and R^(Vb) are each independently selected from hydrogen,        alkenyl, and alkyl;    -   each V¹⁰ is independently fused bicycliccycloalkyl, which is        optionally substituted with one or more groups independently        selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl,        heterocycle, heteroaryl, hydroxy, and NR^(Va)R^(Vb)C(═O)O—;        R^(Va) and R^(Vb) are each independently selected from hydrogen,        alkenyl, and alkyl;    -   each V¹¹ is independently fused bicycliccycloalkylalkyl, which        is optionally substituted with one or more groups independently        selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl,        heterocycle, heteroaryl, hydroxy, and NR^(Va)R^(Vb)C(═O)O—;        R^(Va) and R^(Vb) are each independently selected from hydrogen,        alkenyl, and alkyl;    -   each V¹² is independently bridged-bicycliccycloalkyl, which is        optionally substituted with one or more groups independently        selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl,        heterocycle, heteroaryl, hydroxy, and NR^(Va)R^(Vb)C(═O)O—;        R^(Va) and R^(Vb) are each independently selected from hydrogen,        alkenyl, and alkyl;    -   each V¹³ is independently bridged-bicyclic-cycloalkylalkyl,        which is optionally substituted with one or more groups        independently selected from cycloalkyl, alkoxy, haloalkoxy,        cycloalkenyl, heterocycle, heteroaryl, hydroxy, and        NR^(Va)R^(Vb)C(═O)O—; R^(Va) and R^(Vb) are each independently        selected from hydrogen, alkenyl, and alkyl;    -   each V¹⁴ is independently aryloxyalkyl, which is optionally        substituted with one or more groups independently selected from        cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle,        heteroaryl, hydroxy, and NR^(Va)R^(Vb)C(═O)O—; R^(Va) and R^(Vb)        are each independently selected from hydrogen, alkenyl, and        alkyl;    -   each V¹⁵ is independently arylalkoxyalkyl, which is optionally        substituted with one or more groups independently selected from        cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle,        heteroaryl, hydroxy, and NR^(Va)R^(Vb)C(═O)O—; R^(Va) and R^(Vb)        are each independently selected from hydrogen, alkenyl, and        alkyl;    -   each V¹⁶ is independently cycloalkyloxyalkyl, which is        optionally substituted with one or more groups independently        selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl,        heterocycle, heteroaryl, hydroxy, and NR^(Va)R^(Vb)C(═O)O—;        R^(Va) and R^(Vb) are each independently selected from hydrogen,        alkenyl, and alkyl;    -   each V¹⁷ is independently cycloalkylalkyloxyalkyl, which is        optionally substituted with one or more groups independently        selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl,        heterocycle, heteroaryl, hydroxy, and NR^(Va)R^(Vb)C(═O)O—;        R^(Va) and R^(Vb) are each independently selected from hydrogen,        alkenyl, and alkyl;    -   each V is independently heterocyclooxyalkyl, which is optionally        substituted with one or more groups independently selected from        cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle,        heteroaryl, hydroxy, and NR^(Va)R^(Vb)C(═O)O—; R^(Va) and R^(Vb)        are each independently selected from hydrogen, alkenyl, and        alkyl;    -   each V¹⁹ is independently heterocycloalkyloxyalkyl, which is        optionally substituted with one or more groups independently        selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl,        heterocycle, heteroaryl, hydroxy, and NR^(Va)R^(Vb)C(═O)O—;        R^(Va) and R^(Vb) are each independently selected from hydrogen,        alkenyl, and alkyl;    -   each V is independently heteroaryloxyalkyl, which is optionally        substituted with one or more groups independently selected from        cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle,        heteroaryl, hydroxy, and NR^(Va)R^(Vb)C(═O)O—; R^(Va) and R^(Vb)        are each independently selected from hydrogen, alkenyl, and        alkyl;    -   each V²¹ is independently heteroarylalkyloxyalkyl, which is        optionally substituted with one or more groups independently        selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl,        heterocycle, heteroaryl, hydroxy, and NR^(Va)R^(Vb)C(═O)O—;        R^(Va) and R^(Vb) are each independently selected from hydrogen,        alkenyl, and alkyl;    -   each V is independently cycloalkenylalkyl;    -   each V²³ is independently arylalkyl, wherein the aryl is        substituted with one or more groups independently selected from        cycloalkyl, alkenyl, cycloalkylalkyl, cyanoalkyl, cycloalkoxy,        hydroxyalkoxy, —C(═O)NR^(X)R^(Y), S(═O)₂NR^(X)R^(Y),        alkylsulfanyl, alkylsulfonyl, haloalkylsulfanyl,        haloalkylsulfonyl, alkylsulfonylalkyl, alkylsulfonylalkyl,        arylsulfanyl, arylsulfonyl, alkoxyalkoxy, alkynyl, aryloxy,        heteroaryloxy, alkylsulfonylamino;        -   R^(X) and R^(Y) are independently selected from hydrogen,            alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl,            unsubstituted arylalkoxycarbonyl, unsubstituted arylalkyl,            unsubstituted cycloalkyl, unsubstituted heterocyclyl, and            (NR^(X′)R^(Y′))carbonyl, wherein R^(X′) and R^(Y′) are            independently selected from hydrogen and alkyl;    -   each V is independently heterocycloalkyl, wherein the        heterocycle is substituted with one or more groups independently        selected from cycloalkyl, alkenyl, cycloalkylalkyl, cyanoalkyl,        cycloalkoxy, hydroxyalkoxy, —C(═O)NR^(X)R^(Y),        S(═O)₂NR^(X)R^(Y), alkylsulfanyl, alkylsulfonyl,        haloalkylsulfanyl, haloalkylsulfonyl, alkylsulfonylalkyl,        alkylsulfonylalkyl, arylsulfanyl, arylsulfonyl, alkoxyalkyoxy,        alkynyl, aryloxy, heteroaryloxy, alkylfulfonylamino;        -   R^(X) and R^(Y) are independently selected from hydrogen,            alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl,            unsubstituted arylalkoxycarbonyl, unsubstituted arylalkyl,            unsubstituted cycloalkyl, unsubstituted heterocyclyl, and            (NR^(X)R^(Y))carbonyl, wherein R^(X′) and R^(Y′) are            independently selected from hydrogen and alkyl;    -   each T¹ is independently a spiro, branched or fused        bicycloalkyl;    -   each T² is independently aryl;    -   each T³ is independently heteroaryl;    -   each T⁴ is independently arylalkyl;    -   each T⁵ is independently haloalkyl;    -   each T⁶ is independently heteroarylalkyl;    -   each T⁷ is independently heterocycle; and    -   each T⁸ is independently heterocycloalkyl;    -   or a pharmaceutically acceptable salt, or prodrug thereof.

In one embodiment, the compound of Formula I is Formula Ia:

-   -   wherein:

-   -   -   each V is independently alkyl;        -   L is benzimidazolyl;        -   M is a 5-membered heteroaryl ring;        -   each P is independently selected from:

and

-   -   R′″ is hydrogen or methyl; or a pharmaceutically acceptable        salt, or prodrug thereof.

In one embodiment, the compound of Formula I or Ia is:

-   -   or a pharmaceutically acceptable salt thereof. This compound is        also known as ledipasvir.

In one embodiment, the NS5A inhibitor is a compound described in PCTPublication No. WO2013/075029, which is hereby incorporated by referencein its entirety. In one embodiment, the NS5A inhibitor is a compound ofFormula II:E^(1a)-V^(1a)—C(═O)—P^(1a)—W^(1a)—P^(1b)—C(═O)—V^(1b)-E^(1b)   II

-   -   wherein        -   W^(1a) is

-   -   and W^(1a) is optionally substituted with one or more groups        independently selected from halo, alkyl, haloalkyl, or cyano;        -   Y⁵ is —O—CH₂—, or —CH₂—O—;        -   X⁵ is —CH₂—CH₂— or —CH═CH—;        -   E^(1a) is —N(H)(alkoxycarbonyl), —N(H)(cycloalkylcarbonyl)    -   or —N(H)(cycloalkyloxycarbonyl); or E^(1a)-V^(1a) taken together        are R^(9a);        -   E^(1b) is —N(H)(alkoxycarbonyl), —N(H)(cycloalkylcarbonyl)    -   or —N(H)(cycloalkyloxycarbonyl); or E^(1b)-V^(1b) taken together        are R^(9b);        -   V^(1a) and V^(1b) are each independently selected from:

-   -   -   P^(1a) is selected from:

-   -   -   P^(1b) is selected from:

-   -   and        -   R^(9a) and R^(9b) are each independently:

-   -   -   or a pharmaceutically acceptable salt or prodrug thereof.

In one embodiment, the compound of Formula II is:

-   -   or a pharmaceutically acceptable salt thereof. This compound is        also known as velpatasvir.

B. NS5B Inhibitors

In one embodiment, the NS5B inhibitor are compounds found in PCTPublication No. WO2008/121634, which is incorporated by reference in itsentirety. Additional NS5B inhibitors may be found in U.S. Pat. No.7,429,572, WO 2011/123645, WO 2010/135569, U.S. Pat. Nos. 8,841,275,8,716,262, 8,551,973, 8,173,621, all of which are incorporated byreference in their entirety. In one embodiment, the NS5B inhibitor is acompound of Formula III (described in WO2008/121634):

-   -   wherein    -   (a) R¹ is hydrogen, n-alkyl; branched alkyl; cycloalkyl; or        aryl, which includes, but is not limited to, phenyl or naphthyl,        where phenyl or naphthyl are optionally substituted with at        least one of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        alkoxy, F, Cl, Br, I, nitro, cyano, C₁₋₆ haloalkyl, —N(R^(1′))₂,        C₁₋₆ acylamino, —NHSO₂C₁₋₆ alkyl, —SO₂(R^(1′))₂, COR^(1″), and        —SO₂C₁₋₆ alkyl; (R^(1′) is independently hydrogen or alkyl,        which includes, but is not limited to, C₁₋₂₀ alkyl, C₁₋₁₀ alkyl,        or C₁₋₆ alkyl, R^(1″) is —OR′ or —N(R^(1′))₂);    -   (b) R² is hydrogen, C₁₋₁₀ alkyl, R^(3a) or R^(3b) and R²        together are (CH₂)_(n) so as to form a cyclic ring that includes        the adjoining N and C atoms, C(O)CR^(3a)R^(3b)NHR¹, where n is 2        to 4 and R¹, R^(3a), and R^(3b);    -   (c) R^(3a) and R^(3b) are (i) independently selected from        hydrogen, C₁₋₁₀ alkyl, cycloalkyl, —(CH₂)_(c)(NR³)₂, C₁₋₆        hydroxyalkyl, —CH₂SH, —(CH₂)₂S(O)_(d)Me, —(CH₂)₃NHC(═NH)NH₂,        (1H-indol-3-yl)methyl, (1H-imidazol-4-yl)methyl,        —(CH₂)_(e)COR^(3″), aryl and aryl C₁₋₃ alkyl, said aryl groups        optionally substituted with a group selected from hydroxyl,        C₁₋₁₀ alkyl, C₁₋₆ alkoxy, halogen, nitro and cyano; (ii) R^(3a)        and R^(3b) both are C₁₋₆ alkyl; (iii) R^(3a) and R^(3b) together        are (CH₂)_(f) so as to form a spiro ring; (iv) R^(3a) is        hydrogen and R^(3b) and R² together are (CH₂)_(n) so as to form        a cyclic ring that includes the adjoining N and C atoms (v)        R^(3b) is hydrogen and R^(3a) and R² together are (CH₂)_(n) so        as to form a cyclic ring that includes the adjoining N and C        atoms, where c is 1 to 6, d is 0 to 2, e is 0 to 3, f is 2 to 5,        n is 2 to 4, and where R³ is independently hydrogen or C₁₋₆        alkyl and R³ is —OR′ or —N(R^(3′))₂); (vi) R^(3a) is H and        R^(3b) is H, CH₃, CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃,        CH₂Ph, CH₂-indol-3-yl, —CH₂CH₂SCH₃, CH₂CO₂H, CH₂C(O)NH₂,        CH₂CH₂COOH, CH₂CH₂C(O)NH₂, CH₂CH₂CH₂CH₂NH₂,        —CH₂CH₂CH₂NHC(NH)NH₂, CH₂-imidazol-4-yl, CH₂OH, CH(OH)CH₃,        CH₂((4′-OH)-Ph), CH₂SH, or lower cycloalkyl; or (viii) R^(3a) is        CH₃, —CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂Ph,        CH₂-indol-3-yl, —CH₂CH₂SCH₃, CH₂CO₂H, CH₂C(O)NH₂, CH₂CH₂COOH,        CH₂CH₂C(O)NH₂, CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂NHC(NH)NH₂,        CH₂-imidazol-4-yl, CH₂OH, CH(OH)CH₃, CH₂((4′-OH)-Ph), CH₂SH, or        lower cycloalkyl and R^(3b) is H, where R³ is independently        hydrogen or alkyl, which includes, but is not limited to, C₁₋₂₀        alkyl, C₁₋₁₀ alkyl, or C₁₋₆ alkyl, R³ is —OR′ or —N(R³)₂);    -   (d) R⁴ is hydrogen, C₁₋₁₀ alkyl, C₁₋₁₀ alkyl optionally        substituted with a lower alkyl, alkoxy, di(lower alkyl)-amino,        or halogen, C₁₋₁₀ haloalkyl, C₃₋₁₀ cycloalkyl, cycloalkyl alkyl,        cycloheteroalkyl, aminoacyl, aryl, such as phenyl, heteroaryl,        such as, pyridinyl, substituted aryl, or substituted heteroaryl;    -   (e) R⁵ is H, a lower alkyl, CN, vinyl, O-(lower alkyl), hydroxyl        lower alkyl, i.e., —(CH₂)_(p)OH, where p is 1-6, including        hydroxyl methyl (CH₂OH), CH₂F, N₃, CH₂CN, CH₂NH₂, CH₂NHCH₃,        CH₂N(CH₃)₂, alkyne (optionally substituted), or halogen,        including F, Cl, Br, or I, with the provisos that when X is OH,        base is cytosine and R⁶ is H, R⁵ cannot be N₃ and when X is OH,        R⁶ is CH₃ or CH₂F and B is a purine base, R⁵ cannot be H;    -   (f) R⁶ is H, CH₃, CH₂F, CHF₂, CF₃, F, or CN;    -   (g) X is H, OH, F, OMe, halogen, NH₂, or N₃;    -   (h) Y is OH, H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, vinyl,        N₃, CN, Cl, Br, F, I, NO₂, OC(O)O(C₁₋₄ alkyl), OC(O)O(C₁₋₄        alkyl), OC(O)O(C₁₋₄ alkynyl), OC(O)O(C₂₋₄ alkenyl), OC₁₋₁₀        haloalkyl, O(aminoacyl), O(C₁₋₁₀ acyl), O(C₁₋₄ alkyl), O(C₂₋₄        alkenyl), S(C₁₋₄ acyl), S(C₁₋₄ alkyl), S(C₂₋₄ alkynyl), S(C₂₋₄        alkenyl), SO(C₁₋₄ acyl), SO(C₁₋₄ alkyl), SO(C₂₋₄ alkynyl),        SO(C₂₋₄ alkenyl), SO₂(C₁₋₄ acyl), SO₂(C₁₋₄ alkyl), SO₂(C₂₋₄        alkynyl), SO₂(C₂₋₄ alkenyl), OS(O)₂(C₁₋₄ acyl), OS(O)₂(C₁₋₄        alkyl), OS(O)₂(C₂₋₄ alkenyl), NH₂, NH(C₁₋₄ alkyl), NH(C₂₋₄        alkenyl), NH(C₂₋₄ alkynyl), NH(C₁₋₄ acyl), N(C₁₋₄ alkyl)₂,        N(C₁₋₁₈ acyl)₂, wherein alkyl, alkynyl, alkenyl and vinyl are        optionally substituted by N₃, CN, one to three halogen (Cl, Br,        F, I), NO₂, C(O)O(C₁₋₄ alkyl), C(O)O(C₁₋₄ alkyl), C(O)O(C₁₋₄        alkynyl), C(O)O(C₂₋₄ alkenyl), O(C₁₋₄ acyl), O(C₁₋₄ alkyl),        O(C₂₋₄ alkenyl), S(C₁₋₄ acyl), S(C₁₋₄ alkyl), S(C₂₋₄ alkynyl),        S(C₂₋₄ alkenyl), SO(C₁₋₄ acyl), SO(C₁₋₄ alkyl), SO(C₂₋₄        alkynyl), SO(C₂₋₄ alkenyl), SO₂(C₁₋₄ acyl), SO₂(C₁₋₄ alkyl),        SO₂(C₂₋₄ alkynyl), SO₂(C₂₋₄ alkenyl), OS(O)₂(C₁₋₄ acyl),        OS(O)₂(C₁₋₄ alkyl), OS(O)₂(C₂₋₄ alkenyl), NH₂, NH(C₁₋₄ alkyl),        NH(C₂₋₄ alkenyl), NH(C₂₋₄ alkynyl), NH(C₁₋₄ acyl), N(C₁₋₄        alkyl)₂, N(C₁₋₄ acyl)₂;    -   the base is a naturally occurring or modified purine or        pyrimidine base represented by the following structures:

-   -   wherein    -   Z is N or CR¹²;    -   R⁷, R⁸, R⁹, R¹⁰, and R^(n) are independently H, F, Cl, Br, I,        OH, OR′, SH, SR′, NH₂, NHR′, NR′₂, lower alkyl of C₁-C₆,        halogenated (F, Cl, Br, I) lower alkyl of C₁-C₆, lower alkenyl        of C₂-C₆, halogenated (F, Cl, Br, I) lower alkenyl of C₂-C₆,        lower alkynyl of C₂-C₆ such as C≡CH, halogenated (F, Cl, Br, I)        lower alkynyl of C₂-C₆, lower alkoxy of C₁-C₆, halogenated (F,        Cl, Br, I) lower alkoxy of C₁-C₆, CO₂H, CO₂R′, CONH₂, CONHR′,        CONR′₂, CH═CHCO₂H, or CH═CHCO₂R′,    -   wherein R′ is an optionally substituted alkyl, which includes,        but is not limited to, an optionally substituted C₁₋₂₀ alkyl, an        optionally substituted C₁₋₁₀ alkyl, an optionally substituted        lower alkyl; an optionally substituted cycloalkyl; an optionally        substituted alkynyl of C₂-C₆, an optionally substituted lower        alkenyl of C₂-C₆, or optionally substituted acyl, which includes        but is not limited to C(O) alkyl, C(O)(C₁₋₂₀ alkyl), C(O)(C₁₋₁₀        alkyl), or C(O)(lower alkyl) or alternatively, in the instance        of NR′₂, each R′ comprise at least one C atom that are joined to        form a heterocycle comprising at least two carbon atoms; and    -   R¹² is H, halogen (including F, Cl, Br, I), OH, OR′, SH, SR′,        NH₂, NHR′, NR′₂, NO₂ lower alkyl of C₁-C₆, halogenated (F, Cl,        Br, I) lower alkyl of C₁-C₆, lower alkenyl of C₂-C₆, halogenated        (F, Cl, Br, I) lower alkenyl of C₂-C₆, lower alkynyl of C₂-C₆,        halogenated (F, Cl, Br, I) lower alkynyl of C₂-C₆, lower alkoxy        of C₁-C₆, halogenated (F, Cl, Br, I) lower alkoxy of C₁-C₆,        CO₂H, CO₂R′, CONH₂, CONHR′, CONR′₂, CH═CHCO₂H, or CH═CHCO₂R′;        with the proviso that when base is represented by the structure        c with R¹¹ being hydrogen, R¹² is not a: (i) —C≡C—H, (ii)        —C≡CH₂, or (iii) —NO₂.

In one embodiment, the compound of Formula III is:

-   -   or a pharmaceutically acceptable salt, or diastereomer or a        mixture of diastereomer thereof.

In one embodiment, the NS5B inhibitor is sofosbuvir.

In another embodiment, the NS5B inhibitor is mericitabine or othercompounds described in PCT Publication No. WO2007/065829, which isincorporated herein by reference.

C. NS3 Inhibitors

In one embodiment, the NS3 inhibitor are compounds found in PCTPublication No. WO 2014/008285, which is incorporated by reference inits entirety. Additional NS3 inhibitors may be found in WO 2006/020276,WO 2007/009109, WO 2008/005565, WO 2009/005676, WO 2009/005677, and WO2014/008285, all of which are incorporated by reference in theirentirety. In one embodiment, the NS3 inhibitor is a compound of FormulaIV (described in WO 2014/008285):

-   -   or a stereoisomer, or a mixture of stereoisomers, or a        pharmaceutically acceptable salt thereof, wherein:    -   J is J¹, J², J³, J⁴, J⁵, J⁶, J⁷, J⁸ or J⁹;    -   is T¹, T², T³, T⁴, T⁵, T⁶, T⁷, T⁸, T⁹, T¹⁰, T¹¹, T¹², T¹³ or        T¹⁴;    -   L is L¹, L², L³, L⁴, L⁵, L⁶, L⁷, L⁸, L⁹ or L¹⁰;    -   X is —O—, —CH₂—, —OC(O)—, —C(O)O—, —C(O)—, —SO₂—, —S(O)—,        —N(R¹⁶)—, —S—, ═N—O— or a bond;    -   A is —C(O)—, —S(O)₂—, a 6-10 membered arylene, 5-10 membered        heteroarylene, or 4-10 membered heterocyclene, wherein any of        said arylene, heterocyclene, or heteroarylene is optionally        substituted with 1-4 Z¹ groups;    -   M is a bond, C₁-C₆ alkylene, —O—, or —N(R¹⁶)—;    -   R¹ is H or F;    -   R³, R⁴, and R⁵ are each independently selected from H or Z¹;    -   Q is Q¹, Q², Q³, Q⁴, Q⁵, Q⁶ or Q⁷;    -   E is E¹, E², E³, E⁴, E⁵, or E⁶;    -   G is —CO₂H, —CONHSO₂Z², tetrazolyl, —CONHP(O)(R¹⁶)₂,        —P(O)(OH)(R¹⁶), and —P(O)(R¹⁶)₂;    -   is U¹, U², U³, U⁴, U⁵, U⁶ or U⁷;    -   J¹ is halogen;    -   J² is —OH and R¹ is H;    -   J³ is —NR¹⁷R¹⁸ and R¹ is H;    -   J⁴ is C₁-C₈ alkyl;    -   J⁵ is C₁-C₈ alkyl substituted with 1-4 Z³ groups;    -   J⁶ is C₃-C₈ carbocyclyl optionally substituted with 1-4 Z³        groups;    -   J⁷ is C₆-C₁₀ aryl, 5-10 membered heteroaryl, or 4-10 membered        heterocyclyl optionally substituted with 1-4 Z³ groups;    -   J⁸ is C₁-C₈ alkoxy optionally substituted with 1-4 Z³ groups and        R¹ is H;    -   J⁹ is C₃-C₈ carbocyclyloxy optionally substituted with 1-4 Z³        groups and R¹ is H;    -   T¹ is C₃-C₈ carbocyclylene that is attached to L and M through        two adjacent carbons;    -   T² is C₃-C₈ carcbocyclene that is attached to L and M through        two adjacent carbons, wherein said carbocyclylene is substituted        with 1-4 C₁-C₈ alkyl groups;    -   T³ is C₃-C₈ carcbocyclene that is attached to L and M through        two adjacent carbons, wherein said carbocyclylene is substituted        with 1-4 halogen atoms and said carbocyclylene is optionally        substituted with 1-4 C₁-C₆ alkyl groups;    -   T⁴ is C₃-C₈ carbocyclene that is attached to L and M through two        adjacent carbons, wherein said carbocyclylene is optionally        substituted with a C₁-C₈ alkyl group, wherein said alkyl group        is optionally substituted with 1-4 Z³ groups;    -   T⁵ is 4-10 membered heterocyclene that is attached to L and M        through two adjacent carbons;    -   T⁶ is 4-10 membered heterocyclene that is attached to L through        a carbon atom and attached to M through an N atom, wherein said        heterocyclene is optionally substituted with 1-4 Z¹ groups;    -   T⁷ is 4-10 membered heterocyclene that is attached to M through        a carbon atom and attached to L through an N atom, wherein said        heterocyclene is optionally substituted with 1-4 Z¹ groups;    -   T⁸ is 4-10 membered heterocyclene that is attached to L and M        through two adjacent carbons, wherein said heterocyclene is        optionally substituted with 1-4 Z¹ groups;    -   T⁹ is C₅-C₁₂ spiro bicyclic carbocyclylene that is attached to L        and M through two adjacent carbons, wherein said spiro bicyclic        carbocyclylene is optionally substituted with 1-4 Z¹ groups;    -   T¹⁰ is C₅-C₁₂ fused bicyclic carbocyclylene that is attached to        L and M through two adjacent carbons, wherein said fused        bicyclic carbocyclylene is optionally substituted with 1-4 Z¹        groups;    -   T¹¹ is C₅-C₁₂ bridged bicyclic carbocyclylene that is attached        to L and M through two adjacent carbons, wherein said bridged        bicyclic carbocyclylene is optionally substituted with 1-4 Z¹        groups;    -   T¹² is C₄-C₈ carbocylene that is attached to L and M through two        non-adjacent carbons, wherein said carcbocyclene is optionally        substituted with 1-4 Z¹ groups;    -   T¹³ is a 5-8 membered fused, bridged, or spiro bicyclic        heterocyclene that is attached to L and M through two adjacent        atoms, wherein said heterocyclene is optionally substituted with        1-4 Z¹ groups;    -   T¹⁴ is C₃-C₈ carbocyclylene that is attached to L and M through        two adjacent carbons, wherein said carbocyclylene is optionally        substituted with 1-4 Z⁴ groups;    -   L¹ is C₁-C₈ alkylene or C₂-C₈ alkenylene;    -   L² is C₁-C₈ alkylene or C₂-C₈ alkenylene wherein said C₁-C₈        alkylene is substituted with 1-4 halogens or said C₂-C₈        alkenylene is substituted with 1-4 halogens;    -   L³ is C₁-C₈ alkylene or C₂-C₈ alkenylene wherein said C₁-C₈        alkylene is substituted with 1-4 Z⁴ groups or said C₂-C₈        alkenylene is substituted with 1-4 Z⁴ groups and wherein each is        optionally substituted with 1-4 halogens;    -   L⁴ is C₁-C₈ alkylene or C₂-C₈ alkenylene substituted with two        geminal C₃-C₄ alkyl groups that come together to form a spiro        C₃-C₈ carbocyclyl group, wherein L⁴ is optionally substituted        with 1-4 Z¹ groups;    -   L⁵ is 2-8 membered heteroalkylene or 4-8 membered        heteroalkenylene that is connected to        by an O, S or N atom and said heteroalkylene or heteroalkenylene        is optionally substituted with 1-4 Z³ groups;    -   L⁶ is 2-8 membered heteroalkylene or 5-8 membered        heteroalkenylene that is connected to        by a carbon atom and said heteroalkylene or heteroalkenylene is        substituted with 1-4 halogen atoms and is optionally substituted        with 1-4 Z⁴ groups;    -   L⁷ is 2-8 membered heteroalkylene or 4-8 membered        heteroalkenylene that is connected to        by a carbon atom and said heteroalkylene or heteroalkenylene is        optionally substituted with 1-4 Z⁴ groups;    -   L⁸ is L^(8A)-L^(8B)-L^(8C) wherein L and L are each        independently selected from C₁-C₆ alkylene, C₁-C₆        heteroalkylene, C₂-C₆ alkenylene or a bond and L is a 3- to        6-membered saturated or unsaturated ring containing 0 to 3        heteroatoms selected from N, O, or S, wherein L^(8A) and L^(8C)        connect to L^(8B) at two different ring atoms and L^(8B) is        optionally substituted with 1-4 Z¹ groups;    -   L⁹ is C₂-C₈ alkynylene optionally substituted with 1-4 Z¹        groups;    -   L¹⁰ is C₁-C₈ alkylene or C₃-C₈ alkenylene substituted with two        geminal Z¹ groups that come together to form a spiro 4-8        membered heterocyclyl group, wherein L¹⁰ is optionally        substituted with 1-4 Z¹ groups;    -   U¹ is C₆-C₁₄ membered arylene optionally substituted with 1-4 W        groups;    -   U² is C₃-C₈ membered carbocyclylene optionally substituted with        1-4 W groups;    -   U³ is 4-14 membered heterocyclene optionally substituted with        1-4 W groups that are located on one or more ring atoms selected        from C or N;    -   U⁴ is 5 or 6 membered monocyclic heteroarylene containing 1, 2        or 3 heteroatoms independently selected from N, O, or S, wherein        said heteroarylene is optionally substituted with 1-4 W groups        that are located on one or more ring atoms selected from C or N;    -   U⁵ is 8, 9 or 10 membered fused bicyclic heteroarylene        containing 1, 2 or 3 heteroatom ring atoms independently        selected from N, O, or S, wherein said heteroarylene is        optionally substituted with 1-4 W groups that are located on one        or more ring atoms selected from C or N;    -   U⁶ is 11-14 membered fused tricyclic heteroarylene containing 1,        2, 3 or 4 heteroatom ring atoms independently selected from N,        O, or S, wherein said heteroarylene is optionally substituted        with 1-4 W groups that are located on one or more ring atoms        selected from C or N;    -   U⁷ is 8-10 membered fused bicyclic heteroarylene containing 4        heteroatom ring atoms independently selected from N, O, or S,        wherein said heteroaryl is optionally substituted with 1-2 W        groups that are located on one or more ring atoms selected from        C or N;    -   W is independently W¹, W², W³, W⁴, W⁵, W⁶ or W⁷;    -   W¹ is oxo, halogen, —OR⁶, C₁-C₆ alkyl, —CN, —CF₃, —SR⁶,        —C(O)₂R⁶, —C(O)N(R⁶)₂, —C(O)R⁶, —N(R⁶)C(O)R⁶, —SO₂(C₁-C₆ alkyl),        —S(O)(C₁-C₆ alkyl), C₃-C₈ carbocyclyl, C₃-C₈ cycloalkoxy, C₁-C₆        haloalkyl, —N(R⁶)₂, —NR⁶(C₁-C₆ alkyl)O(C₁-C₆ alkyl), halo(C₁-C₆        alkoxy), —NR⁶SO₂R⁶, —SO₂N(R⁶)₂, —NHCOOR⁶, —NHCONHR⁶, C₆-C₁₀        aryl, 5-14 membered heteroaryl, 4-10 membered heterocyclyl or        —O(4-10 membered heterocyclyl), wherein said W¹ alkyl,        carbocyclyl, cycloalkoxy, haloalkyl, haloalkoxy, aryl,        heteroaryl, or heterocyclyl is optionally substituted with 1-4        Z^(1c) groups;    -   each R⁶ is independently selected from H, C₆-C₁₀ aryl or C₁-C₆        alkyl, wherein said aryl or alkyl is optionally substituted with        1 to 4 substituents independently selected from halogen atoms,        C₁-C₆ alkyl, C₆-C₁₀ aryl, C₃-C₈ carbocyclyl, 5-14 membered        heteroaryl, 4-10 membered heterocyclyl, halo(C₁-C₆ alkoxy), —OH,        —O(C₁-C₆ alkyl), —SH, —S(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl),        —N(C₁-C₆ alkyl)₂, —C(O)(C₁-C₆ alkyl), —SO₂N(C₁-C₆ alkyl)₂,        —NHCOO(C₁-C₆ alkyl), —NHCO(C₁-C₆ alkyl), —NHCONH(C₁-C₆ alkyl),        —CO₂(C₁-C₆ alkyl), or —C(O)N(C₁-C₆ alkyl)₂;    -   W² is C₁-C₆ alkoxy substituted with a 5-14 membered heteroaryl        or C₆-C₁₀ aryl; wherein said heteroaryl or aryl is substituted        with 1-4 Z¹ groups;    -   W³ is C₂-C₆ alkynyl substituted with an C₆-C₁₀ aryl, C₃-C₈        carbocyclyl, C₁-C₈ alkyl, C₁-C₆ haloalkyl, 4-10 membered        heterocyclyl, or 5-14 membered heteroaryl; wherein said aryl,        carbocyclyl, alkyl, haloalkyl, heterocyclyl, or heteroaryl is        optionally substituted with 1-4 Z¹ groups;    -   W⁴ is —SF₅;    -   W⁵ is —O(C₂-C₆ alkyl)OR²² wherein R²² is an C₆-C₁₀ aryl, 5-14        membered heteroaryl or 4-10 membered heterocyclyl, and wherein        said aryl, heteroaryl or heterocyclyl is optionally substituted        with 1-4 Z¹ groups;    -   W⁶ is —O(C₂-C₆ alkyl)NR¹⁶R²² wherein R²² is an C₆-C₁₀ aryl, 5-14        membered heteroaryl or 4-membered heterocyclyl, and wherein said        aryl, heteroaryl or heterocyclyl is optionally substituted with        1-4 Z¹ groups;    -   W⁷ is —O(5-14 membered heteroaryl); wherein said —O(5-14        membered heteroaryl) is optionally substituted with 1-4 Z¹        groups;    -   E¹ is C₂-C₆ alkenyl;    -   E² is C₁-C₆ alkyl;    -   E³ is C₁-C₆ haloalkyl;    -   E⁴ is C₂-C₆ haloalkenyl;    -   E⁵ is C₃-C₆ carbocyclyl;    -   E⁶ is C₁-C₆ alkyl substituted with —OCH₃, —OCD₃, —OCF₃, or        —OCF₂H;    -   Q¹ is H, C₁-C₈ alkyl, C₃-C₈ carbocyclyl, C₆-C₁₀ aryl, 5-6        membered heteroaryl, or 5-6 membered heterocyclyl, wherein when        Q¹ is not H, said Q¹ is optionally substituted with 1-3        substituents independently selected from halogen, —OR⁶, —SR⁶,        —N(R⁶)₂, C₆-C₁₀ aryl, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆        haloalkoxy, —CN,    -   —CF₃, —SO₂(C₁-C₆ alkyl), —S(O)(C₁-C₆ alkyl), —NR⁶SO₂Z²,    -   —SO₂NR¹⁷R¹⁸, —NHCOOR¹⁶, —NHCOZ², —NHCONHR¹⁶, —CO₂R⁶,    -   —C(O)R⁶, or —CON(R⁶)₂;    -   Q² is C₅-C₁₀ spiro bicyclic carbocyclyl optionally substituted        with 1-4 Z¹ groups;    -   Q³ is C₅-C₁₀ fused bicyclic carbocyclyl optionally substituted        with 1-4 Z¹ groups;    -   Q⁴ is C₅-C₁₀ bridged bicyclic carbocyclyl optionally substituted        with 1-4 Z¹ groups;    -   Q⁵ is 4-membered heterocyclyl having 1 heteroatom selected from        N, O or S wherein Q⁵ is optionally substituted with alkyl or 1-4        Z³ groups;    -   Q⁶ is C₁-C₈ alkyl, C₃-C₈ carbocyclyl, C₆-C₁₀ aryl, 5-6 membered        heteroaryl, or 5-6 membered heterocyclyl, wherein Q⁶ is        substituted with 1 oxo group and with 0 to 3 substituents        independently selected from halogen, —OR⁶, —SR⁶, —N(R⁶)₂, C₆-C₁₀        aryl, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, —NO₂, —CN,        —CF₃, —SO₂(C₁-C₆ alkyl),    -   —S(O)(C₁-C₆ alkyl), —NR⁶SO₂Z², —SO₂NR¹⁷R¹⁸, —NHCOOR¹⁶,    -   —NHCOZ², —NHCONHR¹⁶, —CO₂R⁶, —C(O)R⁶, or —CON(R⁶)₂;    -   Q⁷ is C₃-C₈ carbocyclyl, wherein Q⁷ is substituted with 4-8 F        atoms and each carbon of Q⁷ is substituted with 0-2 F atoms;    -   each Z¹ is independently oxo, halogen, C₁-C₈ alkyl, C₂-C₈        alkenyl, C₂-C₈ alkynyl, C₃-C₈ carbocyclyl, C₅-C₁₀ bicyclic        carbocyclyl, C₁-C₈ haloalkyl, C₆-C₁₀ aryl, 5-14 membered        heteroaryl, 4-10 membered heterocyclyl, —CN, —C(O)R¹⁶,        —C(O)OR¹⁶, —C(O)NR¹⁷R¹⁸, —NR¹⁷R¹⁸, —NR¹⁶C(O)R¹⁶,        —NR¹⁶C(O)NR¹⁷R¹⁸, —NR¹⁶S(O)₂R¹⁶,    -   —NR¹⁶S(O)₂NR¹⁷R¹⁸, —NR¹⁶S(O)₂OR¹⁶, —OR¹⁶, —OC(O)R¹⁶,    -   —OC(O)NR¹⁷R¹⁸, —SR¹⁶, —S(O)R¹⁶, —S(O)₂R¹⁶ or —S(O)₂NR¹⁷R¹⁸        wherein any alkyl, alkenyl, alkynyl, carbocyclyl, aryl,        heteroaryl or heterocyclyl of Z¹ is optionally substituted with        1-4 Z^(1a) groups;    -   each Z^(1a) is independently oxo, halogen, C₂-C₈ alkenyl, C₂-C₈        alkynyl, C₃-C₈ carbocyclyl, C₅-C₁₀ bicyclic carbocyclyl, C₁-C₈        haloalkyl, C₆-C₁₀ aryl, 5-14 membered heteroaryl, 4-10 membered        heterocyclyl,    -   —CN, —C(O)R¹⁶, —C(O)OR¹⁶, —C(O)NR¹⁷R¹⁸, —NR¹⁷R¹⁸,    -   —NR¹⁶C(O)R¹⁶, —NR¹⁶C(O)OR¹⁶, —NR¹⁶C(O)NR¹⁷R¹⁸, —NR¹⁶S(O)₂R¹⁶,        —NR¹⁶S(O)₂NR¹⁷R¹⁸, —NR¹⁶S(O)₂OR¹⁶, —OR¹⁶, —OC(O)R¹⁶,        —OC(O)NR¹⁷R¹⁸, —SR¹⁶, —S(O)R¹⁶, —S(O)₂R¹⁶ or —S(O)₂NR¹⁷R¹⁸        wherein any alkenyl, alkynyl, carbocyclyl, aryl, heteroaryl or        heterocyclyl of Z^(1a) is optionally substituted with 1-4 Z^(1c)        groups;    -   each R¹⁶ is independently H, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈        alkynyl, C₃-C₈ carbocyclyl, C₅-C₁₀ bicyclic carbocyclyl, C₆-C₁₀        aryl, 5-14 membered heteroaryl or 4-10 membered heterocyclyl,        wherein any alkyl, alkenyl, alkynyl, carbocyclyl, aryl,        heteroaryl or heterocyclyl of R¹⁶ is optionally substituted with        1-4 Z^(1c) groups;    -   each Z^(1c) is independently oxo, halogen, C₁-C₈ alkyl, C₃-C₈        carbocyclyl, C₅-C₁₀ bicyclic carbocyclyl, C₁-C₈ haloalkyl,        C₆-C₁₀ aryl, 5-14 membered heteroaryl, 4-10 membered        heterocyclyl, —CN, —C(O)(C₁-C₈ alkyl), —C(O)O(C₁-C₈ alkyl),        —C(O)N(C₁-C₈ alkyl)₂, —NH₂, —NH(C₁-C₈ alkyl), —N(C₁-C₈ alkyl)₂,        —NHC(O)O(C₁-C₈ alkyl), —NHC(O)(C₁-C₈ alkyl), —NHC(O)NH(C₁-C₈        alkyl), —OH, —O(C₁-C₈ alkyl), C₃-C₈ cycloalkoxy, C₅-C₁₀ bicyclic        carbocyclyloxy, —S(C₁-C₈ alkyl) or    -   —S(O)₂N(C₁-C₈ alkyl)₂ wherein any alkyl, carbocyclyl, aryl,        heteroaryl, heterocyclyl or cycloalkoxy portion of Z^(1c) is        optionally substituted with 1-4 halogen atoms or C₁-C₆ alkoxy        groups;    -   R¹⁷ and R¹⁸ are each independently H, C₁-C₈ alkyl, C₂-C₈        alkenyl, C₂-C₈ alkynyl, C₃-C₈ carbocyclyl, C₅-C₁₀ bicyclic        carbocyclyl, —C(O)R¹⁶,    -   —C(O)OR¹⁶, C₆-C₁₀ aryl, 5-14 membered heteroaryl or 4-10        membered heterocyclyl, wherein any alkyl, alkenyl, alkynyl,        carbocyclyl, aryl, heteroaryl or heterocyclyl of R or R is        optionally substituted with 1-4 Z^(1c) groups, or R¹⁷ and R¹⁸        together with the nitrogen to which they are attached form a 4-7        membered heterocyclyl group, wherein said 4-7 membered        heterocyclyl group is optionally substituted with 1-4 Z^(1c)        groups;    -   each Z² is independently C₁-C₈ alkyl, C₃-C₈ carbocyclyl, C₅-C₁₀        bicyclic carbocyclyl, C₆-C₁₀ aryl, 5-14 membered heteroaryl,        4-10 membered heterocyclyl, —NR¹⁷R¹⁸ or —OR¹⁶ wherein any alkyl,        carbocyclyl, aryl, heteroaryl or heterocyclyl portion of Z² is        optionally substituted with 1-4 Z^(2a) groups;    -   each Z^(2a) is independently oxo, halogen, C₁-C₈ alkyl, C₂-C₈        alkynyl, C₃-C₈ carbocyclyl, C₅-C₁₀ bicyclic carbocyclyl, C₁-C₈        haloalkyl, C₆-C₁₀ aryl, 5-14 membered heteroaryl, 4-10 membered        heterocyclyl, —(C₂-C₈ alkynyl)aryl, —(C₂-C₈ alkynyl)heteroaryl,        —CN, —C(O)(C₁-C₆ alkyl),    -   —C(O)O(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, —NH₂, —NH(C₁-C₆        alkyl),    -   —N(C₁-C₆ alkyl)₂, —NHC(O)O(C₁-C₆ alkyl), —NHC(O)(C₁-C₆ alkyl),    -   —NHC(O)NH(C₁-C₆ alkyl), —OH, —O(C₁-C₆ alkyl), halo(C₁-C₆        alkoxy), C₃-C₈ cycloalkoxy, —S(C₁-C₆ alkyl), or —SO₂N(C₁-C₆        alkyl)₂; wherein any alkyl, alkynyl, carbocyclyl, cycloalkoxy,        aryl, heteroaryl or heterocyclyl portions of Z^(2a) is        optionally substituted with 1-4 halogen or C₁-C₆ alkoxy groups;    -   each Z³ is independently oxo, halogen, C₂-C₈ alkenyl, C₂-C₈        alkynyl, C₃-C₈ carbocyclyl, C₅-C₁₀ bicyclic carbocyclyl, C₁-C₈        haloalkyl, C₆-C₁₀ aryl, 5-14 membered heteroaryl, 4-10 membered        heterocyclyl, —CN, —C(O)OR¹⁶, —C(O)NR¹⁷R¹⁸, —NR¹⁷R¹⁸,        —NR¹⁶C(O)NR¹⁷R¹⁸, —OR¹⁶,    -   —SR¹⁶ or —SO₂R¹⁶; wherein any alkenyl, alkynyl, carbocyclyl,        aryl, heteroaryl or heterocyclyl portions of Z³ is optionally        substituted with 1-4 halogen; and    -   each Z⁴ is independently oxo, C₂-C₈ alkenyl, C₂-C₈ alkynyl,        C₃-C₈ carbocyclyl, C₅-C₁₀ bicyclic carbocyclyl, C₁-C₈ haloalkyl,        C₆-C₁₀ aryl, 5-14 membered heteroaryl, 4-10 membered        heterocyclyl,    -   —CN, —C(O)OR¹⁶, —C(O)NR¹⁷R¹⁸, —NR¹⁷R¹⁸, —NR¹⁶C(O)NR¹⁷R¹⁸,    -   —OR¹⁶, —SR¹⁶ or —SO₂R¹⁶, wherein any alkenyl, alkynyl,        carbocyclyl, aryl, heteroaryl or heterocyclyl portions of Z⁴ is        optionally substituted with 1-4 halogen.

In one embodiment, the compound of Formula IV is:

-   -   or a pharmaceutically acceptable salt thereof. This compound is        also known as voxilaprevir.

D. Example Anti-HBV Agents

An anti-HBV agent may be a compound that inhibits HBV infection, geneexpression, DNA production, or DNA replication. In one embodiment, theanti-HBV agent is a HBV reverse transcriptase inhibitor. In oneembodiment, the anti-HBV agent is a nucleoside analogue. Non-limitingexamples of anti-HBV agent include tenofovir alafenamide, tenofovir,lamivudine, adefovir, telbivudine and entecavir.

Tenofovir, or tenofovir disoproxil, is a nucleotide analogreverse-transcriptase inhibitor (NtRTI). Tenofovir selectively inhibitsviral reverse transcriptase. Once incorporated into a growing DNAstrand, tenofovir causes premature termination of DNA transcription,preventing viral replication. Tenofovir has a chemical name ofbis{[(isopropoxycarbonyl)oxy]methyl}({[(2R)-1-(6-amino-9H-purin-9-yl)-2-propanyl]oxy}methyl)phosphonate, andthe structure of:

Tenofovir is commercially available under the tradename Viread™. Therecommended dose, in adults and pediatric patients ≥12 years of age (≥35kg), is one 300 mg tablet, once daily, taken orally, without regard tofood.

Tenofovir alafenamide is a nucleotide reverse transcriptase inhibitorand a prodrug of tenofovir. Tenofovir alafenamide has a chemical name ofisopropyl(2S)-2-[[[(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methyl-phenoxy-phosphoryl]amino]propanoate,and the structure of:

Tenofovir alafenamide is commercially available under the tradenameVemlidy™. The recommended dose in adults is one 25 mg tablet once daily,taken orally with food.

Lamivudine is an analogue of cytidine. It can inhibit the reversetranscriptase of hepatitis B virus. It is phosphorylated to activemetabolites that compete for incorporation into viral DNA. The lack of a3′—OH group in the incorporated nucleoside analogue prevents theformation of the 5′ to 3′ phosphodiester linkage essential for DNA chainelongation, and therefore, the viral DNA growth is terminated.Lamivudine has the chemical name of4-Amino-1-[(2R,5S)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-1,2-dihydropyrimidin-2-oneand the structure of:

Lamivudine is commercially available under the tradename Epivir™. Therecommended dose in HBV patients is one 100 mg tablet once daily.

Adefovir is a reverse transcriptase inhibitor. It has a chemical name of{[2-(6-amino-9H-purin-9-yl)ethoxy]methyl}phosphonic acid and thestructure of:

Adefovir is commercially available under the tradename Hepsera™. Therecommended dose is 10 mg orally once daily, without regard to food.

Telbivudine is a synthetic thymidine β-L-nucleoside analogue. It is theL-isomer of thymidine. Telbivudine impairs hepatitis B virus (HBV) DNAreplication by leading to chain termination. It differs from the naturalnucleotide only with respect to the location of the sugar and basemoieties, taking on a levorotatory configuration versus a dextrorotatoryconfiguration as do the natural deoxynucleosides. Telbivudine has achemical name of1-[(2S,4R,5S)-4-hydroxy-5-hydroxymethyltetrahydorfuran-2-yl]-5-methyl-1-H-pyrimidine-2,4-dioneand the structure of:

The recommended dose of telbivudine 600 mg once daily with or withoutfood.

Entecavir is a nucleoside analog, and more specifically a deoxyguanosineanalogue that inhibits reverse transcription, DNA replication andtranscription in the viral replication process. Entecavir reduces theamount of HBV in the blood by reducing its ability to multiply andinfect new cells. Entecavir has a chemical name of2-Amino-9-[(1S,3R,4S)-4-hydroxy-3-(hydroxymethyl)-2-methylidenecyclopentyl]-1H-purin-6-oneand the structure of:

Entecavir is commercially available under the trade name Baraclude™. Therecommended dose for entecavir in adults with chronic HVB infection is0.5 mg or 1 mg daily.

E. Alternative Compounds

It is to be noted that all isomers (including stereoisomers,enantiomers, and diastereomers) and racemic mixtures, tautomers,isotopes, salts, pharmaceutically acceptable salts, polymorphs,pseudopolymorphs, prodrugs and metabolites are embraced by the presentdisclosure.

The term “stereoisomer” as used herein refers to the stereochemicaldefinitions and conventions used herein generally follow S. P. Parker,Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill BookCompany, New York; and Eliel, E. and Wilen, S., Stereochemistry ofOrganic Compounds (1994) John Wiley & Sons, Inc., New York.

The term “chiral” refers to molecules which have the property ofnon-superimposability of the mirror image partner, while the term“achiral” refers to molecules which are superimposable on their mirrorimage partner.

“Isomers” are different compounds that have the same molecular formula.Isomers include stereoisomers, enantiomers and diastereomers.

“Diastereomers” are stereoisomers that have at least two asymmetricatoms, but which are not mirror-images of each other.

“Enantiomers” are a pair of stereoisomers that are non-superimposablemirror images of each other. A 1:1 mixture of a pair of enantiomers is a“racemic” mixture. The term “(±)” is used to designate a racemic mixturewhere appropriate.

The term “stereoisomers” refers to compounds which have identicalchemical constitution, but differ with regard to the arrangement of theatoms or groups in space.

The compounds disclosed herein may have chiral centers, e.g., chiralcarbon atoms. Such compounds thus include racemic mixtures of allstereoisomers, including enantiomers, diastereomers, and atropisomers.In addition, the compounds disclosed herein include enriched or resolvedoptical isomers at any or all asymmetric, chiral atoms. In other words,the chiral centers apparent from the depictions are provided as thechiral isomers or racemic mixtures.

Both racemic and diastereomeric mixtures, as well as the individualoptical isomers isolated or synthesized, substantially free of theirenantiomeric or diastereomeric partners, are all within the scope of thedisclosure. The racemic mixtures can be separated into their individual,substantially optically pure isomers through well-known techniques suchas, for example, the separation of diastereomeric salts formed withoptically active adjuncts, e.g., acids or bases followed by conversionback to the optically active substances. The desired optical isomer canalso be synthesized by means of stereospecific reactions, beginning withthe appropriate stereoisomer of the desired starting material.

It is to be understood that for compounds disclosed herein when a bondis drawn in a non-stereochemical manner (e.g., flat) the atom to whichthe bond is attached includes all stereochemical possibilities. It isalso to be understood that when a bond is drawn in a stereochemicalmanner (e.g., bold, bold-wedge, dashed or dashed-wedge) the atom towhich the stereochemical bond is attached has the stereochemistry asshown unless otherwise noted.

Accordingly, in one embodiment, a compound disclosed herein is greaterthan 50% a single enantiomer. In another embodiment, a compounddisclosed herein is at least 80% a single enantiomer. In anotherembodiment, a compound disclosed herein is at least 90% a singleenantiomer. In another embodiment, a compound disclosed herein is atleast 98% a single enantiomer. In another embodiment, a compounddisclosed herein is at least 99% a single enantiomer. In anotherembodiment, a compound disclosed herein is greater than 50% a singlediastereomer. In another embodiment, a compound disclosed herein is atleast 80% a single diastereomer. In another embodiment, a compounddisclosed herein is at least 90% a single diastereomer. In anotherembodiment, a compound disclosed herein is at least 98% a singlediastereomer. In another embodiment, a compound disclosed herein is atleast 99% a single diastereomer.

The compounds disclosed herein can also exist as tautomeric isomers incertain cases. Although only one delocalized resonance structure may bedepicted, all such forms are contemplated within the scope of thedisclosure. For example, ene-amine tautomers can exist for purine,pyrimidine, imidazole, guanidine, amidine, and tetrazole systems and alltheir possible tautomeric forms are within the scope of the disclosure.

It is understood by one skilled in the art that this disclosure alsoincludes any compound claimed that may be enriched at any or all atomsabove naturally occurring isotopic ratios with one or more isotopes suchas, but not limited to, deuterium (²H or D). As a non-limiting example,a —CH₃ group may be replaced by —CD₃.

Specific values listed below for radicals, substituents, and ranges arefor illustration only; they do not exclude other defined values or othervalues within defined ranges for the radicals and substituents.

Examples of pharmaceutically acceptable salts of the compounds disclosedherein include salts derived from an appropriate base, such as an alkalimetal (for example, sodium), an alkaline earth metal (for example,magnesium), ammonium and NX₄ ⁺ (wherein X is C₁-C₄ alkyl).Pharmaceutically acceptable salts of a nitrogen atom or an amino groupinclude for example salts of organic carboxylic acids such as acetic,benzoic, lactic, fumaric, tartaric, maleic, malonic, malic, isethionic,lactobionic and succinic acids; organic sulfonic acids, such asmethanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonicacids; and inorganic acids, such as hydrochloric, hydrobromic, sulfuric,phosphoric and sulfamic acids. Pharmaceutically acceptable salts of acompound of a hydroxy group include the anion of said compound incombination with a suitable cation such as Na⁺ and NX₄ ⁺ (wherein each Xis independently selected from H or a C₁-C₄ alkyl group).

For therapeutic use, salts of active ingredients of the compoundsdisclosed herein will typically be pharmaceutically acceptable, i.e.,they will be salts derived from a physiologically acceptable acid orbase. However, salts of acids or bases which are not pharmaceuticallyacceptable may also find use, for example, in the preparation orpurification of the compounds described herein or a stereoisomer, or amixture of stereoisomers, or another compound disclosed herein. Allsalts, whether or not derived from a physiologically acceptable acid orbase, are within the scope of the present disclosure.

Metal salts typically are prepared by reacting the metal hydroxide witha compound disclosed herein. Examples of metal salts which are preparedin this way are salts containing Li⁺, Na⁺, and K⁺. A less soluble metalsalt can be precipitated from the solution of a more soluble salt byaddition of the suitable metal compound.

In addition, salts may be formed from acid addition of certain organicand inorganic acids, e.g., HCl, HBr, H₂SO₄, H₃PO₄ or organic sulfonicacids, to basic centers, such as amines.

Finally, it is to be understood that the compositions herein comprisecompounds disclosed herein in their un-ionized, as well as zwitterionicform, and combinations with stoichiometric amounts of water as inhydrates.

The compounds described herein and their pharmaceutically acceptablesalts may exist as different polymorphs or pseudopolymorphs. As usedherein, crystalline polymorphism means the ability of a crystallinecompound to exist in different crystal structures. The crystallinepolymorphism may result from differences in crystal packing (packingpolymorphism) or differences in packing between different conformers ofthe same molecule (conformational polymorphism). As used herein,crystalline pseudopolymorphism means the ability of a hydrate or solvateof a compound to exist in different crystal structures. Thepseudopolymorphs of the instant disclosure may exist due to differencesin crystal packing (packing pseudopolymorphism) or due to differences inpacking between different conformers of the same molecule(conformational pseudopolymorphism). The instant disclosure comprisesall polymorphs and pseudopolymorphs of the compounds described hereinand their pharmaceutically acceptable salts.

The compounds described herein and their pharmaceutically acceptablesalts may also exist as an amorphous solid. As used herein, an amorphoussolid is a solid in which there is no long-range order of the positionsof the atoms in the solid. This definition applies as well when thecrystal size is two nanometers or less. Additives, including solvents,may be used to create the amorphous forms of the instant disclosure. Theinstant disclosure comprises all amorphous forms of the compoundsdescribed herein and their pharmaceutically acceptable salts.

For therapeutic use, salts of active ingredients of the compounds of thedisclosure will be physiologically acceptable, i.e. they will be saltsderived from a physiologically acceptable acid or base. However, saltsof acids or bases which are not physiologically acceptable may also finduse, for example, in the preparation or purification of aphysiologically acceptable compound. All salts, whether or not derivedform a physiologically acceptable acid or base, are within the scope ofthe present disclosure.

Finally, it is to be understood that the compositions herein comprisecompounds of the disclosure in their un-ionized, as well as zwitterionicform, and combinations with stoichiometric amounts of water as inhydrates.

The compounds described herein may have chiral centers, e.g. chiralcarbon or phosphorus atoms. The compounds of the disclosure thus includeracemic mixtures of all stereoisomers, including enantiomers,diastereomers, and atropisomers. In addition, the compounds of thedisclosure include enriched or resolved optical isomers at any or allasymmetric, chiral atoms. In other words, the chiral centers apparentfrom the depictions are provided as the chiral isomers or racemicmixtures. Both racemic and diastereomeric mixtures, as well as theindividual optical isomers isolated or synthesized, substantially freeof their enantiomeric or diastereomeric partners, are all within thescope of the disclosure. The racemic mixtures are separated into theirindividual, substantially optically pure isomers through well-knowntechniques such as, for example, the separation of diastereomeric saltsformed with optically active adjuncts, e.g., acids or bases followed byconversion back to the optically active substances. In most instances,the desired optical isomer is synthesized by means of stereospecificreactions, beginning with the appropriate stereoisomer of the desiredstarting material.

“Prodrug” refers to any compound that when administered to a biologicalsystem generates the drug substance, or active ingredient, as a resultof spontaneous chemical reaction(s), enzyme catalyzed chemicalreaction(s), photolysis, and/or metabolic chemical reaction(s). Aprodrug is thus a covalently modified analog or latent form of atherapeutically active compound. Non-limiting examples of prodrugsinclude ester moieties, quaternary ammonium moieties, glycol moieties,and the like.

Also falling within the scope of this disclosure are the in vivometabolic products of the compounds described herein, to the extent suchproducts are novel and unobvious over the prior art. Such products mayresult for example from the oxidation, reduction, hydrolysis, amidation,esterification and the like of the administered compound, primarily dueto enzymatic processes. Accordingly, the disclosure includes novel andunobvious compounds produced by a process comprising contacting acompound of this disclosure with a mammal for a period of timesufficient to yield a metabolic product thereof. Such products typicallyare identified by preparing a radiolabelled (e.g. ¹⁴C or ³H) compound ofthe disclosure, administering it parenterally in a detectable dose (e.g.greater than about 0.5 mg/kg) to an animal such as rat, mouse, guineapig, monkey, or to man, allowing sufficient time for metabolism to occur(typically about 30 seconds to 30 hours) and isolating its conversionproducts from the urine, blood or other biological samples. Theseproducts are easily isolated since they are labeled (others are isolatedby the use of antibodies capable of binding epitopes surviving in themetabolite). The metabolite structures are determined in conventionalfashion, e.g. by MS or NMR analysis. In general, analysis of metabolitesis done in the same way as conventional drug metabolism studieswell-known to those skilled in the art. The conversion products, so longas they are not otherwise found in vivo, are useful in diagnostic assaysfor therapeutic dosing of the compounds of the disclosure even if theypossess no anti hepatitis B virus activity of their own.

Recipes and methods for determining stability of compounds in surrogategastrointestinal secretions are known. Compounds are defined herein asstable in the gastrointestinal tract where less than about 50 molepercent of the protected groups are deprotected in surrogate intestinalor gastric juice upon incubation for 1 hour at 37° C. Simply because thecompounds are stable to the gastrointestinal tract does not mean thatthey cannot be hydrolyzed in vivo. The prodrugs of the disclosuretypically will be stable in the digestive system but may besubstantially hydrolyzed to the parental drug in the digestive lumen,liver or other metabolic organ, or within cells in general.

For both the inhibitors, whenever a compound described herein issubstituted with more than one of the same designated group, e.g., “R”or “R¹”, then it will be understood that the groups may be the same ordifferent, i.e., each group is independently selected. Wavy lines,

, indicate the site of covalent bond attachments to the adjoiningsubstructures, groups, moieties, or atoms.

Selected substituents comprising the compounds described herein arepresent to a recursive degree. In this context, “recursive substituent”means that a substituent may recite another instance of itself. Becauseof the recursive nature of such substituents, theoretically, a largenumber of compounds may be present in any given embodiment. For example,R^(x) comprises a R^(y) substituent. R^(y) can be R. R can be Z³. Z³ canbe Z⁴ and Z⁴ can be R or comprise substituents comprising R^(y).Alternatively, Z³ can be Z⁵ which can comprise substituents comprisingRy. One of ordinary skill in the art of medicinal chemistry understandsthat the total number of such substituents is reasonably limited by thedesired properties of the compound intended. Such properties include, byway of example and not limitation, physical properties such as molecularweight, solubility or log P, application properties such as activityagainst the intended target, and practical properties such as ease ofsynthesis.

By way of example and not limitation, Z³ and R^(y) are recursivesubstituents in certain embodiments. Typically, each recursivesubstituent can independently occur 20, 19, 18, 17, 16, 15, 14, 13, 12,11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, or 0, times in a given embodiment.More typically, each recursive substituent can independently occur 12 orfewer times in a given embodiment. Even more typically, each recursivesubstituent can independently occur 3 or fewer times in a givenembodiment. For example, Z³ will occur 0 to 8 times, R^(y) will occur 0to 6 times in a given embodiment. Even more typically, Z³ will occur 0to 6 times and R^(y) will occur 0 to 4 times in a given embodiment.

Recursive substituents are an intended aspect of the disclosure. One ofordinary skill in the art of medicinal chemistry understands theversatility of such substituents. To the degree that recursivesubstituents are present in an embodiment of the disclosure, the totalnumber will be determined as set forth above.

The compounds of the present disclosure can be prepared by methods knownto one of skill in the art or based on the examples in the publicationscited herein.

III. DEFINITIONS

Unless stated otherwise, the following terms and phrases as used hereinare intended to have the following meanings:

When a cyclic group (e.g. cycloalkyl, carbocyclyl, bicyclic carbocyclyl,heteroaryl, heterocyclyl) is limited by a number or range of numbers,the number or numbers refer to the number of atoms making up the cyclicgroup, including any heteroatoms. Therefore, for example, a 4-8 memberedheterocyclyl group has 4, 5, 6, 7 or 8 ring atoms.

“Alkenyl” refers to a straight or branched chain hydrocarbyl with atleast one site of unsaturation, e.g., a (sp²)carbon-(sp²)carbon doublebond. For example, an alkenyl group can have 2 to 8 carbon atoms (i.e.,C₂-C₈ alkenyl), or 2 to 6 carbon atoms (i.e., C₂-C₆ alkenyl). Examplesof suitable alkenyl groups include, but are not limited to, ethylene orvinyl (—CH═CH₂) and allyl (—CH₂CH═CH₂).

“Alkenylene” refers to an alkene having two monovalent radical centersderived by the removal of two hydrogen atoms from the same or twodifferent carbon atoms of a parent alkene. Exemplary alkenylene radicalsinclude, but are not limited to, 1,2-ethenylene (—CH═CH—) orprop-1-enylene (—CH₂CH═CH—).

“Alkoxy” is RO— where R is alkyl, as defined herein. Non-limitingexamples of alkoxy groups include methoxy, ethoxy and propoxy.

“Alkyl” refers to a saturated, straight or branched chain hydrocarbylradical. For example, an alkyl group can have 1 to 8 carbon atoms (i.e.,(C₁-C₈) alkyl) or 1 to 6 carbon atoms (i.e., (C₁-C₆ alkyl) or 1 to 4carbon atoms. Examples of alkyl groups include, but are not limited to,methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl,hexyl, heptyl, octyl, nonyl and decyl.

“Alkylene” refers to an alkyl having two monovalent radical centersderived by the removal of two hydrogen atoms from the same or twodifferent carbon atoms of a parent alkane. Examples of alkylene radicalsinclude, but are not limited to, methylene (—CH₂—), ethylene (—CH₂CH₂—),propylene (—CH₂CH₂CH₂—) and butylene (—CH₂CH₂CH₂CH₂—).

“Alkynyl” refers to a straight or branched chain hydrocarbon with atleast one site of unsaturation, e.g., a (sp)carbon-(sp)carbon triplebond. For example, an alkynyl group can have 2 to 8 carbon atoms (C₂-C₈alkyne) or 2 to 6 carbon atoms (C₂-C₆ alkynyl). Examples of alkynylgroups include, but are not limited to, acetylenyl (—C≡CH) and propargyl(—CH₂C≡CH) groups.

“Alkynylene” refers to an alkynyl having two monovalent radical centersderived by the removal of two hydrogen atoms from the same or twodifferent carbon atoms of a parent alkyne. Typical alkynylene radicalsinclude, but are not limited to, acetylene (—C≡C—), propargylene(—CH₂C≡C—), and 1-pentynylene (—CH₂CH₂CH₂C≡C—).

“Aryl” refers to a single all carbon aromatic ring or a multiplecondensed all carbon ring system (e.g., a fused multicyclic ring system)wherein at least one of the rings is aromatic. For example, an arylgroup can have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12carbon atoms. It is to be understood that the point of attachment of amultiple condensed ring system, as defined above, can be at any positionof the ring system including an aromatic or a carbocyclyl portion of thering. Examples of aryl groups include, but are not limited to, phenyl,naphthyl, tetrahydronaphthyl and indanyl.

“Arylene” refers to an aryl as defined herein having two monovalentradical centers derived by the removal of two hydrogen atoms from twodifferent carbon atoms of a parent aryl. Typical arylene radicalsinclude, but are not limited to, phenylene, e.g.,

and naphthylene, e.g.,

“Bicyclic carbocyclyl” refers to a 5-14 membered saturated or partiallyunsaturated bicyclic fused, bridged, or spiro ring hydrocarbon attachedvia a ring carbon. In a spiro bicyclic carbocyclyl, the two rings sharea single common carbon atom. In a fused bicyclic carbocyclyl, the tworings share two common and adjacent carbon atoms. In a bridged bicycliccarbocyclyl, the two rings share three or more common, non-adjacentcarbon atoms. Examples of bicyclic carbocyclyl groups include, but arenot limited to spiro bicyclic carbocyclyl groups wherein two carbocyclylrings share one common atom

fused bicyclic carbocyclyl groups wherein two carbocyclyl rings sharetwo common atoms

and bridged bicyclic carbocyclyl groups wherein two carbocyclyl ringsshare three or more (such as 3, 4, 5 or 6) common atoms

“Bicyclic carbocyclylene” refers to a bicyclic carbocyclyl, as definedabove, having two monovalent radical centers derived from the removal oftwo hydrogen atoms from the same or two different carbon atom of aparent bicyclic carbocyclyl. Examples of bicyclic carbocyclylene groupsinclude, but are not limited to, spiro bicyclic carbocyclylene groupswherein two carbocyclyl rings share one common atom

fused bicyclic carbocyclylene groups wherein two carbocyclyl rings sharetwo common atoms

and bridged bicyclic carbocyclylene groups wherein two carbocyclyl ringsshare three or more (such as 3, 4, 5 or 6) common atoms

“Carbocyclyloxy” is RO— where R is carbocyclyl, as defined herein.

“Bicyclic carbocyclyloxy” is RO— where R is bicyclic carbocyclyl, asdefined herein.

“Carbocyclyl”, and “carbocycle” refers to a hydrocarbyl group containingone saturated or partially unsaturated ring structure, attached via aring carbon. In various embodiments, carbocyclyl refers to a saturatedor a partially unsaturated C₃-C₁₂ cyclic moiety, examples of whichinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl,cyclohexenyl, cycloheptyl and cyclooctyl.

“Carbocyclylene” (as well as “carbocyclene”) refers to a carbocyclyl, asdefined herein, having two monovalent radical centers derived by theremoval of two hydrogen atoms from the same or two different carbonatoms of a parent carbocyclyl. Examples of carbocyclene include, but arenot limited to, cyclopropylene, cyclobutylene, cyclopentylene andcyclohexylene.

“Carbocyclylalkyl” refers to a hydrocarbyl group containing onesaturated or partially unsaturated ring structure attached to an alkylgroup, attached via a ring carbon or an alkyl carbon. In variousembodiments, carbocyclylalkyl refers to a saturated or a partiallyunsaturated C₁-C₁₂ carbocyclylalkyl moiety, examples of which includecyclopropylalkyl, cyclobutylalkyl, cyclopropylethyl, andcyclopropylpropyl.

“Carbocyclylalkylene” refers to a carbocyclylalkyl, as defined herein,having two monovalent radical centers derived by the removal of twohydrogen atoms from the same or two different carbon atoms of a parentcycloalkylalkyl. Examples of cycloalkylene include, but are not limitedto, cyclopropylmethylene and cyclopropylmethylene.

“Cycloalkyl” refers to a hydrocarbyl group containing one saturated ringstructure, attached via a ring carbon. In various embodiments,cycloalkyl refers to a saturated C₃-C₁₂ cyclic moiety, examples of whichinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyland cyclooctyl.

“Cycloalkoxy” is RO— where R is cycloalkyl, as defined herein.

“Direct bond” refers a covalent bond between two atoms.

“Halo” or “halogen” refers to chloro (—Cl), bromo (—Br), fluoro (—F) oriodo (—I).

“Haloalkenyl” refers to alkenyl group, as defined herein, substitutedwith one or more halogen atoms.

“Haloalkoxy” refers to alkoxy, as defined herein, substituted with oneor more halogen atoms.

“Haloalkyl” refers to an alkyl group, in which one or more hydrogenatoms of the alkyl group is replaced with a halogen atom. Examples ofhaloalkyl groups include, but are not limited to, —CF₃, —CHF₂, —CFH₂ and—CH₂CF₃.

“Haloalkylene” refers to alkylene group, as defined herein, substitutedwith one or more halogen atoms.

“Heteroalkyl” refers to an alkyl group, as defined herein, in which oneor more carbon atoms is replaced with an oxygen, sulfur, or nitrogenatom.

“Heteroalkylene” refers to an alkylene group, as defined herein, inwhich one or more carbon atoms is replaced with an oxygen, sulfur, ornitrogen atom.

“Heteroalkenyl” refers to an alkenyl group, as defined herein, in whichone or more carbon atoms is replaced with an oxygen, sulfur, or nitrogenatom.

“Heteroalkenylene” refers to heteroalkenyl group, as defined above,having two monovalent radical centers derived by the removal of twohydrogen atoms from the same or two different atoms of a parentheteroalkenyl group.

“Heteroaryl” refers to a single aromatic ring that has at least one atomother than carbon in the ring, wherein the atom is selected from thegroup consisting of oxygen, nitrogen and sulfur; the term also includesmultiple condensed ring systems that have at least one such aromaticring. For example, heteroaryl includes monocyclic, bicyclic or tricyclicring having up to 6 atoms in each ring, wherein at least one ring isaromatic and contains from 1 to 4 heteroatoms in the ring selected fromthe group consisting of oxygen, nitrogen and sulfur. The rings of themultiple condensed ring system can be connected to each other via fused,spiro and bridged bonds when allowed by valency requirements.Non-limiting examples of heteroaryl include pyridyl, thienyl, furanyl,pyrimidyl, imidazolyl, pyranyl, pyrazolyl, thiazolyl, thiadiazolyl,isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, pyridazinyl, pyrazinyl,quinolinyl, isoquinolinyl, quinoxalinyl, benzofuranyl, dibenzofuranyl,dibenzothiophenyl, benzothienyl, indolyl, benzothiazolyl, benzooxazolyl,benzimidazolyl, isoindolyl, benzotriazolyl, purinyl, thianaphthenyl andpyrazinyl. Attachment of heteroaryl can occur via an aromatic ring, or,if heteroaryl is bicyclic or tricyclic and one of the rings is notaromatic or contains no heteroatoms, through a non-aromatic ring or aring containing no heteroatoms. “Heteroaryl” is also understood toinclude the N-oxide derivative of any nitrogen containing heteroaryl.

“Heteroarylene” refers to a heteroaryl, as defined above, having twomonovalent radical centers derived by the removal of two hydrogen atomsfrom the same or two different carbon atoms or the removal of a hydrogenfrom one carbon atom and the removal of a hydrogen atom from onenitrogen atom of a parent heteroaryl group. Non-limiting examples ofheteroarylene groups are:

“Heterocyclyl” refers to a saturated or partially unsaturatedmonocyclic, bicyclic or tricyclic group of 2 to 14 ring-carbon atomsand, in addition to ring-carbon atoms, 1 to 4 heteroatoms selected fromnitrogen, oxygen and sulfur. Bi- or tricyclic heterocyclyl groups mayhave fused, bridged, or spiro ring connectivity. In various embodimentsthe heterocyclic group is attached to another moiety through carbon orthrough a heteroatom. Examples of heterocyclyl include withoutlimitation azetidinyl, oxazolinyl, isoxazolinyl, oxetanyl,tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydroisoquinolinyl,1,4-dioxanyl, pyrrolidinyl, morpholinyl, thiomorpholinyl,dihydrobenzoimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl,dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl,dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl,dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl,dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl,dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl,dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl,methylenedioxybenzoyl, chromanyl, dihydropyranoquinoxalinyl,tetrahydroquinoxalinyl, tetrahydroquinolinyl, dihydropyranoquinolinyland tetrahydrothienyl and N-oxides thereof. A spiro bicyclicheterocyclyl group refers to a bicyclic heterocyclyl group wherein thetwo rings of the bicyclic heterocyclyl group share one common atom. Afused bicyclic heterocyclyl group refers to a bicyclic heterocyclylgroup wherein the two rings of the bicyclic heterocyclyl group share twocommon atoms. A bridged bicyclic heterocyclyl group refers to a bicyclicheterocyclyl group wherein the two rings of the bicyclic heterocyclylgroup share three or more (such as 3, 4, 5 or 6) common atoms.

“Heterocyclene” refers to a heterocyclyl, as defined herein, having twomonovalent radical centers derived from the removal of two hydrogenatoms from the same or two different carbon atoms, through a carbon anda heteroatom, or through two heteroatoms of a parent heterocycle.

The term “optionally substituted” refers to a moiety wherein allsubstituents are hydrogen or wherein one or more of the hydrogens of themoiety are replaced by non-hydrogen substituents; that is to say themoiety that is optionally substituted is either substituted orunsubstituted.

IV. PHARMACEUTICAL COMPOSITIONS

In certain embodiments, the compounds are administered in pharmaceuticalcompositions. The compounds of this disclosure may be formulated withconventional carriers and excipients, which will be selected in accordwith ordinary practice. Tablets will contain excipients, glidants,fillers, binders and the like. Aqueous formulations are prepared insterile form, and when intended for delivery by other than oraladministration generally will be isotonic. All formulations willoptionally contain excipients such as those set forth in the “Handbookof Pharmaceutical Excipients” (1986). Excipients include ascorbic acidand other antioxidants, chelating agents such as EDTA, carbohydratessuch as dextran, hydroxyalkylcellulose, hydroxyalkylmethylcellulose,stearic acid and the like. The pH of the formulations ranges from about3 to about 11, but is ordinarily about 7 to 10. In some embodiments, thepH of the formulations ranges from about 2 to about 5, but is ordinarilyabout 3 to 4.

While it is possible for the active ingredients to be administered aloneit may be preferable to present them as pharmaceutical compositions. Theformulations, both for veterinary and for human use, of the disclosurecomprise at least one active ingredient, as above defined, together withone or more acceptable carriers therefor and optionally othertherapeutic ingredients, particularly those additional therapeuticingredients as discussed herein. The carrier(s) must be “acceptable” inthe sense of being compatible with the other ingredients of theformulation and physiologically innocuous to the recipient thereof.

The formulations include those suitable for the foregoing administrationroutes. The formulations may conveniently be presented in unit dosageform and may be prepared by any of the methods well known in the art ofpharmacy. Techniques and formulations generally are found in Remington'sPharmaceutical Sciences (Mack Publishing Co., Easton, Pa.). Such methodsinclude the step of bringing into association the active ingredient withthe carrier which constitutes one or more accessory ingredients. Ingeneral the formulations are prepared by uniformly and intimatelybringing into association the active ingredient with liquid carriers orfinely divided solid carriers or both, and then, if necessary, shapingthe product.

Formulations of the present disclosure suitable for oral administrationmay be presented as discrete units such as capsules, cachets or tabletseach containing a predetermined amount of the active ingredient; as apowder or granules; as a solution or a suspension in an aqueous ornon-aqueous liquid; or as an oil-in-water liquid emulsion or awater-in-oil liquid emulsion. The active ingredient may also beadministered as a bolus, electuary or paste.

A tablet is made by compression or molding, optionally with one or moreaccessory ingredients. Compressed tablets may be prepared by compressingin a suitable machine the active ingredient in a free-flowing form suchas a powder or granules, optionally mixed with a binder, lubricant,inert diluent, preservative, surface active or dispersing agent. Moldedtablets may be made by molding in a suitable machine a mixture of thepowdered active ingredient moistened with an inert liquid diluent. Thetablets may optionally be coated or scored and optionally are formulatedso as to provide slow or controlled release of the active ingredienttherefrom.

For infections of the eye or other external tissues e.g. mouth and skin,the formulations are preferably applied as a topical ointment or creamcontaining the active ingredient(s) in an amount of, for example, 0.075to 20% w/w (including active ingredient(s) in a range between 0.1% and20% in increments of 0.1% w/w such as 0.6% w/w, 0.7% w/w, etc.),preferably 0.2 to 15% w/w and most preferably 0.5 to 10% w/w. Whenformulated in an ointment, the active ingredients may be employed witheither a paraffinic or a water-miscible ointment base. Alternatively,the active ingredients may be formulated in a cream with an oil-in-watercream base.

If desired, the aqueous phase of the cream base may include, forexample, at least 30% w/w of a polyhydric alcohol, i.e. an alcoholhaving two or more hydroxyl groups such as propylene glycol, butane1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol(including PEG 400) and mixtures thereof. The topical formulations maydesirably include a compound which enhances absorption or penetration ofthe active ingredient through the skin or other affected areas. Examplesof such dermal penetration enhancers include dimethyl sulphoxide andrelated analogs.

The oily phase of the emulsions of this disclosure may be constitutedfrom known ingredients in a known manner. While the phase may comprisemerely an emulsifier (otherwise known as an emulgent), it desirablycomprises a mixture of at least one emulsifier with a fat or an oil orwith both a fat and an oil. Preferably, a hydrophilic emulsifier isincluded together with a lipophilic emulsifier which acts as astabilizer. It is also preferred to include both an oil and a fat.Together, the emulsifier(s) with or without stabilizer(s) make up theso-called emulsifying wax, and the wax together with the oil and fatmake up the so-called emulsifying ointment base which forms the oilydispersed phase of the cream formulations.

Emulgents and emulsion stabilizers suitable for use in the formulationof the disclosure include Tween® 60, Span® 80, cetostearyl alcohol,benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodiumlauryl sulfate. Further emulgents and emulsion stabilizers suitable foruse in the formulation of the disclosure include Tween® 80.

The choice of suitable oils or fats for the formulation is based onachieving the desired cosmetic properties. The cream should preferablybe a non-greasy, non-staining and washable product with suitableconsistency to avoid leakage from tubes or other containers. Straight orbranched chain, mono- or dibasic alkyl esters such as di-isoadipate,isocetyl stearate, propylene glycol diester of coconut fatty acids,isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate,2-ethylhexyl palmitate or a blend of branched chain esters known asCrodamol CAP may be used, the last three being preferred esters. Thesemay be used alone or in combination depending on the propertiesrequired. Alternatively, high melting point lipids such as white softparaffin and/or liquid paraffin or other mineral oils are used.

Pharmaceutical compositions according to the present disclosure comprisea combination according to the disclosure together with one or morepharmaceutically acceptable carriers or excipients and optionally othertherapeutic agents. Pharmaceutical compositions containing the activeingredient may be in any form suitable for the intended method ofadministration. When used for oral use for example, tablets, troches,lozenges, aqueous or oil suspensions, dispersible powders or granules,emulsions, hard or soft capsules, syrups or elixirs may be prepared.Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsincluding sweetening agents, flavoring agents, coloring agents andpreserving agents, in order to provide a palatable preparation. Tabletscontaining the active ingredient in admixture with non-toxicpharmaceutically acceptable excipient which are suitable for manufactureof tablets are acceptable. These excipients may be, for example, inertdiluents, such as calcium or sodium carbonate, lactose, calcium orsodium phosphate; granulating and disintegrating agents, such as maizestarch, or alginic acid; binding agents, such as starch, gelatin oracacia; and lubricating agents, such as magnesium stearate, stearic acidor talc. Tablets may be uncoated or may be coated by known techniquesincluding microencapsulation to delay disintegration and adsorption inthe gastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate alone or with a wax may be employed.

Formulations for oral use may be also presented as hard gelatin capsuleswhere the active ingredient is mixed with an inert solid diluent, forexample calcium phosphate or kaolin, or as soft gelatin capsules whereinthe active ingredient is mixed with water or an oil medium, such aspeanut oil, liquid paraffin or olive oil.

Aqueous suspensions of the disclosure contain the active materials inadmixture with excipients suitable for the manufacture of aqueoussuspensions. Such excipients include a suspending agent, such as sodiumcarboxymethylcellulose, methylcellulose, hydroxypropyl methylcelluose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia,and dispersing or wetting agents such as a naturally-occurringphosphatide (e.g., lecithin), a condensation product of an alkyleneoxide with a fatty acid (e.g., polyoxyethylene stearate), a condensationproduct of ethylene oxide with a long chain aliphatic alcohol (e.g.,heptadecaethyleneoxycetanol), a condensation product of ethylene oxidewith a partial ester derived from a fatty acid and a hexitol anhydride(e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension mayalso contain one or more preservatives such as ethyl or n-propylp-hydroxy-benzoate, one or more coloring agents, one or more flavoringagents and one or more sweetening agents, such as sucrose or saccharin.Further non-limiting examples of suspending agents include Cyclodextrinand Captisol (═Sulfobutyl ether beta-cyclodextrin; SEB-beta-CD).

Oil suspensions may be formulated by suspending the active ingredient ina vegetable oil, such as arachis oil, olive oil, sesame oil or coconutoil, or in a mineral oil such as liquid paraffin. The oral suspensionsmay contain a thickening agent, such as beeswax, hard paraffin or cetylalcohol. Sweetening agents, such as those set forth above, and flavoringagents may be added to provide a palatable oral preparation. Thesecompositions may be preserved by the addition of an antioxidant such asascorbic acid.

Dispersible powders and granules of the disclosure suitable forpreparation of an aqueous suspension by the addition of water providethe active ingredient in admixture with a dispersing or wetting agent, asuspending agent, and one or more preservatives. Suitable dispersing orwetting agents and suspending agents are exemplified by those disclosedabove. Additional excipients, for example sweetening, flavoring andcoloring agents, may also be present.

The pharmaceutical compositions of the disclosure may also be in theform of oil-in-water emulsions. The oily phase may be a vegetable oil,such as olive oil or arachis oil, a mineral oil, such as liquidparaffin, or a mixture of these. Suitable emulsifying agents includenaturally-occurring gums, such as gum acacia and gum tragacanth,naturally-occurring phosphatides, such as soybean lecithin, esters orpartial esters derived from fatty acids and hexitol anhydrides, such assorbitan monooleate, and condensation products of these partial esterswith ethylene oxide, such as polyoxyethylene sorbitan monooleate. Theemulsion may also contain sweetening and flavoring agents. Syrups andelixirs may be formulated with sweetening agents, such as glycerol,sorbitol or sucrose. Such formulations may also contain a demulcent, apreservative, a flavoring or a coloring agent.

The pharmaceutical compositions of the disclosure may be in the form ofa sterile injectable preparation, such as a sterile injectable aqueousor oleaginous suspension. This suspension may be formulated according tothe known art using those suitable dispersing or wetting agents andsuspending agents which have been mentioned above. The sterileinjectable preparation may also be a sterile injectable solution orsuspension in a non-toxic parenterally acceptable diluent or solvent,such as a solution in 1,3-butane-diol or prepared as a lyophilizedpowder. Among the acceptable vehicles and solvents that may be employedare water, Ringer's solution and isotonic sodium chloride solution. Inaddition, sterile fixed oils may conventionally be employed as a solventor suspending medium. For this purpose any bland fixed oil may beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid may likewise be used in the preparation ofinjectables. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution isotonic sodium chloride solution,and hypertonic sodium chloride solution.

The amount of active ingredient that may be combined with the carriermaterial to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. For example, atime-release formulation intended for oral administration to humans maycontain approximately 1 to 1000 mg of active material compounded with anappropriate and convenient amount of carrier material which may varyfrom about 5 to about 95% of the total compositions (weight:weight). Thepharmaceutical composition can be prepared to provide easily measurableamounts for administration. For example, an aqueous solution intendedfor intravenous infusion may contain from about 3 to 500 μg of theactive ingredient per milliliter of solution in order that infusion of asuitable volume at a rate of about 30 mL/hr can occur.

Formulations suitable for topical administration to the eye also includeeye drops wherein the active ingredient is dissolved or suspended in asuitable carrier, especially an aqueous solvent for the activeingredient. The active ingredient is preferably present in suchformulations in a concentration of 0.5 to 20%, advantageously 0.5 to10%, and particularly about 1.5% w/w.

Formulations suitable for topical administration in the mouth includelozenges comprising the active ingredient in a flavored basis, usuallysucrose and acacia or tragacanth; pastilles comprising the activeingredient in an inert basis such as gelatin and glycerin, or sucroseand acacia; and mouthwashes comprising the active ingredient in asuitable liquid carrier.

Formulations for rectal administration may be presented as a suppositorywith a suitable base comprising for example cocoa butter or asalicylate.

Formulations suitable for intrapulmonary or nasal administration have aparticle size for example in the range of 0.1 to 500 microns, such as0.5, 1, 30, 35 etc., which is administered by rapid inhalation throughthe nasal passage or by inhalation through the mouth so as to reach thealveolar sacs. Suitable formulations include aqueous or oily solutionsof the active ingredient. Formulations suitable for aerosol or drypowder administration may be prepared according to conventional methodsand may be delivered with other therapeutic agents such as compoundsheretofore used in the treatment or prophylaxis of hepatitis B virusinfections as described below.

Formulations suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or spray formulationscontaining in addition to the active ingredient such carriers as areknown in the art to be appropriate.

Formulations suitable for parenteral administration include aqueous andnon-aqueous sterile injection solutions which may contain anti-oxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which may include suspending agents and thickeningagents.

The formulations are presented in unit-dose or multi-dose containers,for example sealed ampoules and vials, and may be stored in afreeze-dried (lyophilized) condition requiring only the addition of thesterile liquid carrier, for example water for injection, immediatelyprior to use. Extemporaneous injection solutions and suspensions areprepared from sterile powders, granules and tablets of the kindpreviously described. Preferred unit dosage formulations are thosecontaining a daily dose or unit daily sub-dose, as herein above recited,or an appropriate fraction thereof, of the active ingredient.

It should be understood that in addition to the ingredients particularlymentioned above the formulations of this disclosure may include otheragents conventional in the art having regard to the type of formulationin question, for example those suitable for oral administration mayinclude flavoring agents.

The disclosure further provides veterinary compositions comprising atleast one active ingredient as above defined together with a veterinarycarrier therefor.

Veterinary carriers are materials useful for the purpose ofadministering the composition and may be solid, liquid or gaseousmaterials which are otherwise inert or acceptable in the veterinary artand are compatible with the active ingredient. These veterinarycompositions may be administered orally, parenterally or by any otherdesired route.

Compounds of the disclosure are used to provide controlled releasepharmaceutical compositions containing as active ingredient one or morecompounds of the disclosure (“controlled release formulations”) in whichthe release of the active ingredient are controlled and regulated toallow less frequency dosing or to improve the pharmacokinetic ortoxicity profile of a given active ingredient.

The inhibitors may be administered as a co-formulation. Methods ofco-formulation are known in the art. For example, the co-formulation ofledipasvir and sofosbuvir is thoroughly described in WO 2014/12098. Inone embodiment, the pharmaceutical composition comprises:

-   -   a) an effective amount of ledipasvir wherein the ledipasvir is        substantially amorphous; and    -   b) an effective amount of sofosbuvir wherein the sofosbuvir is        substantially crystalline, and further wherein the composition        exhibits unexpected properties.

In one embodiment, ledipasvir is formulated as a solid dispersioncomprising ledipasvir dispersed within a polymer matrix formed by apharmaceutically acceptable polymer. In one embodiment, the polymer iscopovidone. In one embodiment, wherein the weight ratio of ledipasvir tocopovidone in the solid dispersion is about 1:1.

In one embodiment, the pharmaceutical composition comprises:

-   -   a) about 40% w/w of sofosbuvir and    -   b) about 18% w/w of the solid dispersion comprising ledipasvir.

In one embodiment, the pharmaceutical composition further comprises:

-   -   a) about 5 to about 25% w/w lactose monohydrate,    -   b) about 5 to about 25% w/w microcrystalline cellulose,    -   c) about 1 to about 10% w/w croscarmellose sodium,    -   d) about 0.5 to about 3% w/w colloidal silicon dioxide, and    -   e) about 0.1 to about 3% w/w magnesium stearate.

Also useful in the methods described herein is a pharmaceutical dosageform comprising the pharmaceutical composition described hereincomprising about 90 mg of ledipasvir and about 400 mg of sofosbuvir. Inone embodiment, the pharmaceutical dosage comprises ledipasvirformulated as a solid dispersion within a polymer matrix of copovidone.In one embodiment, the amount of copovidone is about 90 mg. In oneembodiment, the pharmaceutical dosage form further comprises:

-   -   (a) about 165 mg of lactose monohydrate;    -   (b) about 180 mg of microcrystalline cellulose;    -   (c) about 50 mg of croscarmellose sodium;    -   (d) about 10 mg of colloidal silicon dioxide; and    -   (e) about 15 mg of magnesium stearate.

In one embodiment, the compsoition, co-formulation, or pharmaceuticaldosage form further comprises another anti-HBV agent. In one embodiment,the anti-HBV agent is selected from tenofovir alafenamide, tenofovir,lamivudine, adefovir, telbivudine or entecavir. In one embodiment, theanti-HBV agent is tenofovir alafenamide. In one embodiment, thetenofovir alafenamide is present at an amount of 25 mg. In oneembodiment, the tenofovir alafenamide is present at an amount less than25 mg, such as 20 mg or 15 mg. In one embodiment, the pharmaceuticaldosage form is in the form of a tablet comprising a film coating.

V. ROUTES OF ADMINISTRATION

One or more compounds of the disclosure (herein referred to as theactive ingredients) are administered by any route appropriate to thecondition to be treated. Suitable routes include oral, rectal, nasal,pulmonary, topical (including buccal and sublingual), vaginal andparenteral (including subcutaneous, intramuscular, intravenous,intradermal, intrathecal and epidural), and the like. In certainembodiments, the compounds disclosed herein are administered byintravenous injection. It will be appreciated that the preferred routemay vary with for example the condition of the recipient. An advantageof the compounds of this disclosure is that they are orally bioavailableand can be dosed orally.

Effective dose of active ingredient depends at least on the nature ofthe condition being treated, toxicity, whether the compound is beingused prophylactically (lower doses) or against an active viralinfection, the method of delivery, and the pharmaceutical composition,and will be determined by the clinician using conventional doseescalation studies. It can be expected to be from about 0.0001 to about100 mg/kg body weight per day; typically, from about 0.01 to about 10mg/kg body weight per day; more typically, from about 0.01 to about 5mg/kg body weight per day; most typically, from about 0.05 to about 0.5mg/kg body weight per day. For example, the daily candidate dose for anadult human of approximately 70 kg body weight will range from 1 mg to1000 mg, preferably between 5 mg and 500 mg, and may take the form ofsingle or multiple doses.

In the methods of the present disclosure for the treatment of ahepatitis B virus infection, the compounds of the present disclosure canbe administered at any time to a human who may come into contact withhumans suffering from a hepatitis B virus infection or is alreadysuffering from a hepatitis B virus infection. In some embodiments, thecompounds of the present disclosure can be administered prophylacticallyto humans coming into contact with humans suffering from a hepatitis Bvirus infection. In some embodiments, administration of the compounds ofthe present disclosure can be to humans testing positive for a hepatitisB virus infection but not yet showing symptoms of a hepatitis B virusinfection. In some embodiments, administration of the compounds of thepresent disclosure can be to humans upon commencement of symptoms of ahepatitis B virus infection.

Effective dose of active ingredient depends at least on the nature ofthe condition being treated, toxicity, whether the compound is beingused prophylactically (lower doses) or against an active viralinfection, the method of delivery, and the pharmaceutical composition,and will be determined by the clinician using conventional doseescalation studies. It can be expected to be from about 0.0001 to about100 mg/kg body weight per day; typically, from about 0.01 to about 10mg/kg body weight per day; more typically, from about 0.01 to about 5mg/kg body weight per day; most typically, from about 0.05 to about 0.5mg/kg body weight per day. For example, the daily candidate dose for anadult human of approximately 70 kg body weight will range from 1 mg to1000 mg, preferably between 5 mg and 500 mg, and may take the form ofsingle or multiple doses.

The effective dose of a compound of the present disclosure for treatingthe hepatitis B virus infection can depend on whether the dose is to beused prophylactically or to treat a human already suffering from ahepatitis B virus infection. Moreover, the dose can depend on whetherthe human suffering from a hepatitis B virus infection does not yet showsymptoms or is already showing symptoms of a hepatitis B virusinfection. Larger doses may be necessary for treating humans testingpositive for a hepatitis B virus infection and for humans showingsymptoms of a hepatitis B virus infection as compared to humansreceiving prophylactic treatment.

Any suitable period of time for administration of the compounds of thepresent disclosure is contemplated. For example, administration can befor from 1 day to 100 days, including 2, 3, 4, 5, 6, 7, 8, 9, 10, 15,20, 25, 30, 40, 50, 60, 70, 80, or 90 days. The administration can alsobe for from 1 week to 15 weeks, including 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, or 14 weeks. Longer periods of administration are alsocontemplated. The time for administration can depend on whether thecompound is being administered prophylactically or to treat a humansuffering from an a hepatitis B virus infection. For example, aprophylactic administration can be for a period of time while the humanis in regular contact with other humans suffering from an a hepatitis Bvirus infection, and for a suitable period of time following the lastcontact with a human suffering from an a hepatitis B virus infection.For humans already suffering from an a hepatitis B virus infection, theperiod of administration can be for any length of time necessary totreat the patient and a suitable period of time following a negativetest for a hepatitis B virus infection to ensure the a hepatitis B virusinfection does not return.

In various methods, ledipasvir or another NS5A inhibitor is administeredin an amount ranging from about 10 mg/day to about 200 mg/day. Forexample, the amount of the compound can be about 30 mg/day, about 45mg/day, about 60 mg/day, about 90 mg/day, about 120 mg/day, about 135mg/day, about 150 mg/day, or about 180 mg/day. In some methods,ledipasvir is administered at about 90 mg/day. In various methods, theNS5A inhibitor is administered in an amount ranging from about 50 mg/dayto about 800 mg/day. For example, the amount of the inhibitor can beabout 100 mg/day, about 200 mg/day, or about 400 mg/day.

In various methods, sofosbuvir or another NS5B inhibitor is administeredin an amount ranging from about 10 mg/day to about 1000 mg/day. Forexample, the amount of sofosbuvir can be about 100 mg/day, about 200mg/day, about 300 mg/day, about 400 mg/day, about 500 mg/day, about 600mg/day, about 700 mg/day, about 800 mg/day. In some methods, sofosbuviris administered at about 400 mg/day.

In various methods, the anti-HBV agent is administered in an amountranging from about 10 mg/day to about 1000 mg/day. For example, theamount of tenofovir alafenamide can be about 5 mg/day, about 10 mg/day,about 15 mg/day, about 20 mg/day, about 25 mg/day.

VI. COMBINATION THERAPY

In certain embodiments, a method for treating or preventing an HBVinfection in a human having or at risk of having the infection isprovided, comprising administering to the human a therapeuticallyeffective amount of a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, in combination with a therapeutically effectiveamount of one or more (e.g., one, two, three, four, one or two, one tothree, or one to four) additional therapeutic agents. In one embodiment,a method for treating an HBV infection in a human having or at risk ofhaving the infection is provided, comprising administering to the humana therapeutically effective amount of a compound disclosed herein, or apharmaceutically acceptable salt thereof, in combination with atherapeutically effective amount of one or more (e.g., one, two, three,four, one or two, one to three, or one to four) additional therapeuticagents.

In certain embodiments, the present disclosure provides a method fortreating an HBV infection, comprising administering to a patient in needthereof a therapeutically effective amount of a compound disclosedherein or a pharmaceutically acceptable salt thereof, in combinationwith a therapeutically effective amount of one or more (e.g., one, two,three, four, one or two, one to three, or one to four) additionaltherapeutic agents which are suitable for treating an HBV infection.

In certain embodiments, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with one, two,three, four, or more additional therapeutic agents. In certainembodiments, a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, is combined with two additional therapeuticagents. In other embodiments, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with threeadditional therapeutic agents. In further embodiments, a compounddisclosed herein, or a pharmaceutically acceptable salt thereof, iscombined with four additional therapeutic agents. The one, two, three,four, or more additional therapeutic agents can be different therapeuticagents selected from the same class of therapeutic agents, and/or theycan be selected from different classes of therapeutic agents.

Administration of HBV Combination Therapy

In certain embodiments, when a compound disclosed herein is combinedwith one or more additional therapeutic agents as described above, thecomponents of the composition are administered as a simultaneous orsequential regimen. When administered sequentially, the combination maybe administered in two or more administrations.

Co-administration of a compound disclosed herein with one or moreadditional therapeutic agents generally refers to simultaneous orsequential administration of a compound disclosed herein and one or moreadditional therapeutic agents, such that therapeutically effectiveamounts of each agent are present in the body of the patient.

Co-administration includes administration of unit dosages of thecompounds disclosed herein before or after administration of unitdosages of one or more additional therapeutic agents. The compounddisclosed herein may be administered within seconds, minutes, or hoursof the administration of one or more additional therapeutic agents. Forexample, in some embodiments, a unit dose of a compound disclosed hereinis administered first, followed within seconds or minutes byadministration of a unit dose of one or more additional therapeuticagents. Alternatively, in other embodiments, a unit dose of one or moreadditional therapeutic agents is administered first, followed byadministration of a unit dose of a compound disclosed herein withinseconds or minutes. In some embodiments, a unit dose of a compounddisclosed herein is administered first, followed, after a period ofhours (e.g., 1-12 hours), by administration of a unit dose of one ormore additional therapeutic agents. In other embodiments, a unit dose ofone or more additional therapeutic agents is administered first,followed, after a period of hours (e.g., 1-12 hours), by administrationof a unit dose of a compound disclosed herein.

In certain embodiments, a compound disclosed herein is combined with oneor more additional therapeutic agents in a unitary dosage form forsimultaneous administration to a patient, for example as a solid dosageform for oral administration.

In certain embodiments a compound of Formula (I) is formulated as atablet, which may optionally contain one or more other compounds usefulfor treating HBV. In certain embodiments, the tablet can contain anotheractive ingredient for treating HBV.

In certain embodiments, such tablets are suitable for once daily dosing.

HBV Combination Therapy

In the above embodiments, the additional therapeutic agent may be ananti-HBV agent. For example, the additional therapeutic agent may beselected from the group consisting of HBV combination drugs, other drugsfor treating HBV, 3-dioxygenase (IDO) inhibitors, antisenseoligonucleotide targeting viral mRNA, Apolipoprotein A1 modulator,arginase inhibitors, B- and T-lymphocyte attenuator inhibitors, Bruton'styrosine kinase (BTK) inhibitors, CCR2 chemokine antagonist, CD137inhibitors, CD160 inhibitors, CD305 inhibitors, CD4 agonist andmodulator, compounds targeting HBcAg, compounds targeting hepatitis Bcore antigen (HBcAg), covalently closed circular DNA (cccDNA)inhibitors, cyclophilin inhibitors, cytokines, cytotoxicT-lymphocyte-associated protein 4 (ipi4) inhibitors, DNA polymeraseinhibitor, Endonuclease modulator, epigenetic modifiers, Farnesoid Xreceptor agonist, gene modifiers or editors, HBsAg inhibitors, HBsAgsecretion or assembly inhibitors, HBV antibodies, HBV DNA polymeraseinhibitors, HBV replication inhibitors, HBV RNAse inhibitors, HBVvaccines, HBV viral entry inhibitors, HBx inhibitors, Hepatitis B largeenvelope protein modulator, Hepatitis B large envelope proteinstimulator, Hepatitis B structural protein modulator, hepatitis Bsurface antigen (HBsAg) inhibitors, hepatitis B surface antigen (HBsAg)secretion or assembly inhibitors, hepatitis B virus E antigeninhibitors, hepatitis B virus replication inhibitors, Hepatitis virusstructural protein inhibitor, HIV-1 reverse transcriptase inhibitor,Hyaluronidase inhibitor, IAPs inhibitors, IL-2 agonist, IL-7 agonist,Immunoglobulin agonist, Immunoglobulin G modulator, immunomodulators,indoleamine-2, inhibitors of ribonucleotide reductase, Interferonagonist, Interferon alpha 1 ligand, Interferon alpha 2 ligand,Interferon alpha 5 ligand modulator, Interferon alpha ligand, Interferonalpha ligand modulator, interferon alpha receptor ligands, Interferonbeta ligand, Interferon ligand, Interferon receptor modulator,Interleukin-2 ligand, ipi4 inhibitors, lysine demethylase inhibitors,histone demethylase inhibitors, KDM5 inhibitors, KDM1 inhibitors, killercell lectin-like receptor subfamily G member 1 inhibitors,lymphocyte-activation gene 3 inhibitors, lymphotoxin beta receptoractivators, microRNA (miRNA) gene therapy agents, modulators of Ax1,modulators of B7-H3, modulators of B7-H4, modulators of CD160,modulators of CD161, modulators of CD27, modulators of CD47, modulatorsof CD70, modulators of GITR, modulators of HEVEM, modulators of ICOS,modulators of Mer, modulators of NKG2A, modulators of NKG2D, modulatorsof OX40, modulators of SIRPalpha, modulators of TIGIT, modulators ofTim-4, modulators of Tyro, Na+-taurocholate cotransporting polypeptide(NTCP) inhibitors, natural killer cell receptor 2B4 inhibitors, NOD2gene stimulator, Nucleoprotein inhibitor, nucleoprotein modulators, PD-1inhibitors, PD-L1 inhibitors, PEG-Interferon Lambda, Peptidylprolylisomerase inhibitor, phosphatidylinositol-3 kinase (PI3K) inhibitors,recombinant scavenger receptor A (SRA) proteins, recombinant thymosinalpha-1, Retinoic acid-inducible gene 1 stimulator, Reversetranscriptase inhibitor, Ribonuclease inhibitor, RNA DNA polymeraseinhibitor, short interfering RNAs (siRNA), short synthetic hairpin RNAs(sshRNAs), SLC10A1 gene inhibitor, SMAC mimetics, Src tyrosine kinaseinhibitor, stimulator of interferon gene (STING) agonists, stimulatorsof NOD1, T cell surface glycoprotein CD28 inhibitor, T-cell surfaceglycoprotein CD8 modulator, Thymosin agonist, Thymosin alpha 1 ligand,Tim-3 inhibitors, TLR-3 agonist, TLR-7 agonist, TLR-9 agonist, TLR9 genestimulator, toll-like receptor (TLR) modulators, Viral ribonucleotidereductase inhibitor, zinc finger nucleases or synthetic nucleases(TALENs), and combinations thereof.

In certain embodiments, a compound of Formula (I) is formulated as atablet, which may optionally contain one or more other compounds usefulfor treating HBV. In certain embodiments, the tablet can contain anotheractive ingredient for treating HBV, such as 3-dioxygenase (IDO)inhibitors, Apolipoprotein A1 modulator, arginase inhibitors, B- andT-lymphocyte attenuator inhibitors, Bruton's tyrosine kinase (BTK)inhibitors, CCR2 chemokine antagonist, CD137 inhibitors, CD160inhibitors, CD305 inhibitors, CD4 agonist and modulator, compoundstargeting HBcAg, compounds targeting hepatitis B core antigen (HBcAg),core protein allosteric modulators, covalently closed circular DNA(cccDNA) inhibitors, cyclophilin inhibitors, cytotoxicT-lymphocyte-associated protein 4 (ipi4) inhibitors, DNA polymeraseinhibitor, Endonuclease modulator, epigenetic modifiers, Farnesoid Xreceptor agonist, HBsAg inhibitors, HBsAg secretion or assemblyinhibitors, HBV DNA polymerase inhibitors, HBV replication inhibitors,HBV RNAse inhibitors, HBV viral entry inhibitors, HBx inhibitors,Hepatitis B large envelope protein modulator, Hepatitis B large envelopeprotein stimulator, Hepatitis B structural protein modulator, hepatitisB surface antigen (HBsAg) inhibitors, hepatitis B surface antigen(HBsAg) secretion or assembly inhibitors, hepatitis B virus E antigeninhibitors, hepatitis B virus replication inhibitors, Hepatitis virusstructural protein inhibitor, HIV-1 reverse transcriptase inhibitor,Hyaluronidase inhibitor, IAPs inhibitors, IL-2 agonist, IL-7 agonist,immunomodulators, indoleamine-2 inhibitors, inhibitors of ribonucleotidereductase, Interleukin-2 ligand, ipi4 inhibitors, lysine demethylaseinhibitors, histone demethylase inhibitors, KDM1 inhibitors, KDM5inhibitors, killer cell lectin-like receptor subfamily G member 1inhibitors, lymphocyte-activation gene 3 inhibitors, lymphotoxin betareceptor activators, modulators of Ax1, modulators of B7-H3, modulatorsof B7-H4, modulators of CD160, modulators of CD161, modulators of CD27,modulators of CD47, modulators of CD70, modulators of GITR, modulatorsof HEVEM, modulators of ICOS, modulators of Mer, modulators of NKG2A,modulators of NKG2D, modulators of OX40, modulators of SIRPalpha,modulators of TIGIT, modulators of Tim-4, modulators of Tyro,Na+-taurocholate cotransporting polypeptide (NTCP) inhibitors, naturalkiller cell receptor 2B4 inhibitors, NOD2 gene stimulator, Nucleoproteininhibitor, nucleoprotein modulators, PD-1 inhibitors, PD-L1 inhibitors,Peptidylprolyl isomerase inhibitor, phosphatidylinositol-3 kinase (PI3K)inhibitors, Retinoic acid-inducible gene 1 stimulator, Reversetranscriptase inhibitor, Ribonuclease inhibitor, RNA DNA polymeraseinhibitor, SLC10A1 gene inhibitor, SMAC mimetics, Src tyrosine kinaseinhibitor, stimulator of interferon gene (STING) agonists, stimulatorsof NOD1, T cell surface glycoprotein CD28 inhibitor, T-cell surfaceglycoprotein CD8 modulator, Thymosin agonist, Thymosin alpha 1 ligand,Tim-3 inhibitors, TLR-3 agonist, TLR-7 agonist, TLR-9 agonist, TLR9 genestimulator, toll-like receptor (TLR) modulators, Viral ribonucleotidereductase inhibitor, and combinations thereof.

HBV Combination Drugs

Examples of combination drugs for the treatment of HBV include TRUVADA®(tenofovir disoproxil fumarate and emtricitabine); ABX-203, lamivudine,and PEG-IFN-alpha; ABX-203adefovir, and PEG-IFNalpha; and INO-1800(INO-9112 and RG7944).

Other HBV Drugs

Examples of other drugs for the treatment of HBV includealpha-hydroxytropolones, amdoxovir, beta-hydroxycytosine nucleosides,CCC-0975, elvucitabine, ezetimibe, cyclosporin A, gentiopicrin(gentiopicroside), JNJ-56136379, nitazoxanide, birinapant, NOV-205(molixan, BAM-205), oligotide, mivotilate, feron, GST-HG-131,levamisole, Ka Shu Ning, alloferon, WS-007, Y-101 (Ti Fen Tai),rSIFN-co, PEG-IIFNm, KW-3, BP-Inter-014, oleanolic acid, HepB-nRNA,cTP-5 (rTP-5), HSK-II-2, HEISCO-106-1, HEISCO-106, Hepbarna, IBPB-0061A,Hepuyinfen, DasKloster 0014-01, ISA-204, Jiangantai (Ganxikang),MIV-210, OB-AI-004, PF-06, picroside, DasKloster-0039, hepulantai,IMB-2613, TCM-800B, reduced glutathione, RO-6864018, RG-7834, UB-551,and ZH-2N, and the compounds disclosed in US 2015/0210210682 (Roche), US2016/0122344 (Roche), WO2015173164, and WO2016023877.

HBV Vaccines

HBV vaccines include both prophylactic and therapeutic vaccines.Examples of HBV prophylactic vaccines include Vaxelis, Hexaxim,Heplisav, Mosquirix, DTwP-HBV vaccine, Bio-Hep-B, D/T/P/HBV/M(LBVP-0101; LBVW-0101), DTwP-Hepb-Hib-IPV vaccine, Heberpenta L,DTwP-HepB-Hib, V-419, CVI-HBV-001, Tetrabhay, hepatitis B prophylacticvaccine (Advax Super D), Hepatrol-07, GSK-223192A, ENGERIX B recombinanthepatitis B vaccine (intramuscular, Kangtai Biological Products),recombinant hepatitis B vaccine (Hansenual polymorpha yeast,intramuscular, Hualan Biological Engineering), recombinant hepatitis Bsurface antigen vaccine, Bimmugen, Euforavac, Eutravac,anrix-DTaP-IPV-Hep B, HBAI-20, Infanrix-DTaP-IPV-Hep B-Hib, PentabioVaksin DTP-HB-Hib, Comvac 4, Twinrix, Euvax-B, Tritanrix HB, InfanrixHep B, Comvax, DTP-Hib-HBV vaccine, DTP-HBV vaccine, Yi Tai, HeberbiovacHB, Trivac HB, GerVax, DTwP-Hep B-Hib vaccine, Bilive, Hepavax-Gene,SUPERVAX, Comvac5, Shanvac-B, Hebsulin, Recombivax HB, Revac B mcf,Revac B+, Fendrix, DTwP-HepB-Hib, DNA-001, Shan6, rhHBsAG vaccine, andDTaP-rHB-Hib vaccine.

Examples of HBV therapeutic vaccines include HBsAG-HBIG complex,ARB-1598, Bio-Hep-B, NASVAC, abi-HB (intravenous), ABX-203, Tetrabhay,GX-110E, GS-4774, peptide vaccine (epsilonPA-44), Hepatrol-07, NASVAC(NASTERAP), IMP-321, BEVAC, Revac B mcf, Revac B+, MGN-1333, KW-2,CVI-HBV-002, AltraHepB, VGX-6200, FP-02, FP-02.2, TG-1050, NU-500,HBVax, im/TriGrid/antigen vaccine, Mega-CD40L-adjuvanted vaccine,HepB-v, RG7944 (INO-1800), recombinant VLP-based therapeutic vaccine(HBV infection, VLP Biotech), AdTG-17909, AdTG-17910 AdTG-18202,ChronVac-B, TG-1050, and Lm HBV.

HBV DNA Polymerase Inhibitors

Examples of HBV DNA polymerase inhibitors include adefovir (HEPSERA®),emtricitabine (EMTRIVA®), tenofovir disoproxil fumarate (VIREAD®),tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofoviralafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovirdipivoxil, tenofovir dipivoxil fumarate, tenofovir octadecyloxyethylester, CMX-157, besifovir, entecavir (BARACLUDE®), entecavir maleate,telbivudine (TYZEKA®), pradefovir, clevudine, ribavirin, lamivudine(EPIVIR-HBV®), phosphazide, famciclovir, fusolin, metacavir, SNC-019754,FMCA, AGX-1009, AR-II-04-26, HIP-1302, tenofovir disoproxil aspartate,tenofovir disoproxil orotate, and HS-10234.

Immunomodulators

Examples of immunomodulators include rintatolimod, imidol hydrochloride,ingaron, dermaVir, plaquenil (hydroxychloroquine), proleukin,hydroxyurea, mycophenolate mofetil (MPA) and its ester derivativemycophenolate mofetil (MMF), WF-10, ribavirin, IL-12, INO-9112, polymerpolyethyleneimine (PEI), Gepon, VGV-1, MOR-22, BMS-936559, RO-7011785,RO-6871765, and IR-103.

Toll-Like Receptor (TLR) Modulators

TLR modulators include modulators of TLR1, TLR2, TLR3, TLR4, TLR5, TLR6,TLR7, TLR8, TLR9, TLR10, TLR11, TLR12, and TLR13. Examples of TLR3modulators include rintatolimod, poly-ICLC, RIBOXXON®, Apoxxim,RIBOXXIM®, IPH-33, MCT-465, MCT-475, and ND-1.1.

Examples of TLR7 modulators include GS-9620, GSK-2245035, imiquimod,resiquimod, DSR-6434, DSP-3025, IMO-4200, MCT-465, MEDI-9197, 3M-051,SB-9922, 3M-052, Limtop, TMX-30X, TMX-202, RG-7863, RG-7795, and thecompounds disclosed in US20100143301 (Gilead Sciences), US20110098248(Gilead Sciences), and US20090047249 (Gilead Sciences).

Examples of TLR8 modulators include motolimod, resiquimod, 3M-051,3M-052, MCT-465, IMO-4200, VTX-763, VTX-1463, and the compoundsdisclosed in US20140045849 (Janssen), US20140073642 (Janssen),WO2014/056953 (Janssen), WO2014/076221 (Janssen), WO2014/128189(Janssen), US20140350031 (Janssen), WO2014/023813 (Janssen),US20080234251 (Array Biopharma), US20080306050 (Array Biopharma),US20100029585 (Ventirx Pharma), US20110092485 (Ventirx Pharma),US20110118235 (Ventirx Pharma), US20120082658 (Ventirx Pharma),US20120219615 (Ventirx Pharma), US20140066432 (Ventirx Pharma),US20140088085 (Ventirx Pharma), US20140275167 (Novira Therapeutics), andUS20130251673 (Novira Therapeutics).

Examples of TLR9 modulators include BB-001, BB-006, CYT-003, IMO-2055,IMO-2125, IMO-3100, IMO-8400, IR-103, IMO-9200, agatolimod, DIMS-9054,DV-1079, DV-1179, AZD-1419, leftolimod (MGN-1703), litenimod, andCYT-003-QbG10.

Interferon Alpha Receptor Ligands

Examples of interferon alpha receptor ligands include interferonalpha-2b (INTRON A®), pegylated interferon alpha-2a (PEGASYS®),PEGylated interferon alpha-1b, interferon alpha 1b (HAPGEN®), Veldona,Infradure, Roferon-A, YPEG-interferon alfa-2a (YPEG-rhIFNalpha-2a),P-1101, Algeron, Alfarona, Ingaron (interferon gamma), rSIFN-co(recombinant super compound interferon), Ypeginterferon alfa-2b(YPEG-rhIFNalpha-2b), MOR-22, peginterferon alfa-2b (PEG-INTRON®),Bioferon, Novaferon, Inmutag (Inferon), MULTIFERON@, interferon alfa-n1(HUMOFERON®), interferon beta-1a (AVONEX®), Shaferon, interferon alfa-2b(Axxo), Alfaferone, interferon alfa-2b (BioGeneric Pharma),interferon-alpha 2 (CJ), Laferonum, VIPEG, BLAUFERON-A, BLAUFERON-B,Intermax Alpha, Realdiron, Lanstion, Pegaferon, PDferon-B PDferon-B,interferon alfa-2b (IFN, Laboratorios Bioprofarma), alfainterferona 2b,Kalferon, Pegnano, Feronsure, PegiHep, interferon alfa 2b(Zydus-Cadila), interferon alfa 2a, Optipeg A, Realfa 2B, Reliferon,interferon alfa-2b (Amega), interferon alfa-2b (Virchow),ropeginterferon alfa-2b, rHSA-IFN alpha-2a (recombinant human serumalbumin intereferon alpha 2a fusion protein), rHSA-IFN alpha 2b,recombinant human interferon alpha-(1b, 2a, 2b), peginterferon alfa-2b(Amega), peginterferon alfa-2a, Reaferon-EC, Proquiferon, Uniferon,Urifron, interferon alfa-2b (Changchun Institute of BiologicalProducts), Anterferon, Shanferon, Layfferon, Shang Sheng Lei Tai,INTEFEN, SINOGEN, Fukangtai, Pegstat, rHSA-IFN alpha-2b, and Interapo(Interapa).

Hyaluronidase Inhibitors

Examples of hyaluronidase inhibitors include astodrimer.

Hepatitis B Surface Antigen (HBsAg) Inhibitors

Examples of HBsAg inhibitors include HBF-0259, PBHBV-001, PBHBV-2-15,PBHBV-2-1, REP-9AC, REP-9C, REP-9, REP-2139, REP-2139-Ca, REP-2165,REP-2055, REP-2163, REP-2165, REP-2053, REP-2031 and REP-006, andREP-9AC′.

Examples of HBsAg secretion inhibitors include BM601.

Cytotoxic T-Lymphocyte-Associated Protein 4 (Ipi4) Inhibitors

Examples of Cytotoxic T-lymphocyte-associated protein 4 (ipi4)inhibitors include AGEN-2041, AGEN-1884, ipilumimab, belatacept,PSI-001, PRS-010, Probody mAbs, tremelimumab, and JHL-1155.

Cyclophilin Inhibitors

Examples of cyclophilin inhibitors include CPI-431-32, EDP-494, OCB-030,SCY-635, NVP-015, NVP-018, NVP-019, STG-175, and the compounds disclosedin U.S. Pat. No. 8,513,184 (Gilead Sciences), US20140030221 (GileadSciences), US20130344030 (Gilead Sciences), and US20130344029 (GileadSciences).

HBV Viral Entry Inhibitors

Examples of HBV viral entry inhibitors include Myrcludex B.

Antisense Oligonucleotide Targeting Viral mRNA

Examples of antisense oligonucleotide targeting viral mRNA includeISIS-HBVRx, IONIS-HBVRx, IONIS-GSK6-LRx, GSK-3389404.

Short Interfering RNAs (siRNA) and ddRNAi.

Examples of siRNA include TKM-HBV (TKM-HepB), ALN-HBV, SR-008,HepB-nRNA, and ARC-520, ARC-521, ARB-1740, ARB-1467.

Examples of DNA-directed RNA interference (ddRNAi) include BB-HB-331.

Endonuclease Modulators

Examples of endonuclease modulators include PGN-514.

Ribonucelotide Reductase Inhibitors

Examples of inhibitors of ribonucleotide reductase include Trimidox.

HBV E Antigen Inhibitors

Examples of HBV E antigen inhibitors include wogonin.

Covalently Closed Circular DNA (cccDNA) Inhibitors

Examples of cccDNA inhibitors include BSBI-25, and CHR-101.

Farnesoid X Receptor Agonist

Example of farnesoid x receptor agonist such as EYP-001.

HBV Antibodies

Examples of HBV antibodies targeting the surface antigens of thehepatitis B virus include GC-1102, XTL-17, XTL-19, KN-003, IV HepabulinSN, and fully human monoclonal antibody therapy (hepatitis B virusinfection, Humabs BioMed).

Examples of HBV antibodies, including monoclonal antibodies andpolyclonal antibodies, include Zutectra, Shang Sheng Gan Di, Uman Big(Hepatitis B Hyperimmune), Omri-Hep-B, Nabi-HB, Hepatect CP, HepaGam B,igantibe, Niuliva, CT-P24, hepatitis B immunoglobulin (intravenous, pH4,HBV infection, Shanghai RAAS Blood Products), and Fovepta (BT-088).

Fully human monoclonal antibodies such as HBC-34.

CCR2 Chemokine Antagonists

Examples of CCR2 chemokine antagonists include propagermanium.

Thymosin Agonists

Examples of thymosin agonists include Thymalfasin, recombinant thymosinalpha 1 (GeneScience)

Cytokines

Examples of cytokines include recombinant IL-7, CYT-107, interleukin-2(IL-2, Immunex), recombinant human interleukin-2 (Shenzhen Neptunus),IL-15, IL-21, IL-24, and celmoleukin.

Nucleoprotein Modulators

Nucleoprotein modulators may be either HBV core or capsid proteininhibitors. Examples of nucleoprotein modulators include AT-130, GLS4,NVR-1221, NVR-3778, BAY 41-4109, morphothiadine mesilate, JNJ-379, andDVR-23. Capsid assembly inhibitors such as AB-423.

Examples of capsid inhibitors include the compounds disclosed inUS20140275167 (Novira Therapeutics), US20130251673 (NoviraTherapeutics), US20140343032 (Roche), WO2014037480 (Roche),US20130267517 (Roche), WO2014131847 (Janssen), WO2014033176 (Janssen),WO2014033170 (Janssen), and WO2014033167 (Janssen), WO2015/059212(Janssen), WO2015118057 (Janssen), WO2015011281 (Janssen), WO2014184365(Janssen), WO2014184350 (Janssen), WO2014161888 (Janssen), WO2013096744(Novira), US20150225355 (Novira), US20140178337 (Novira), US20150315159(Novira), US20150197533 (Novira), US20150274652 (Novira), US20150259324,(Novira), US20150132258 (Novira), U.S. Pat. No. 9,181,288 (Novira),WO2014184350 (Janssen), WO2013144129 (Roche).

Retinoic Acid-inducible Gene 1 Stimulators

Examples of stimulators of retinoic acid-inducible gene 1 includeSB-9200, SB-40, SB-44, ORI-7246, ORI-9350, ORI-7537, ORI-9020, ORI-9198,and ORI-7170, RGT-100.

NOD2 Stimulators

Examples of stimulators of NOD2 include SB-9200.

Phosphatidylinositol 3-Kinase (PI3K) Inhibitors

Examples of PI3K inhibitors include idelalisib, ACP-319, AZD-8186,AZD-8835, buparlisib, CDZ-173, CLR-457, pictilisib, neratinib,rigosertib, rigosertib sodium, EN-3342, TGR-1202, alpelisib, duvelisib,IPI-549, UCB-5857, taselisib, XL-765, gedatolisib, ME-401, VS-5584,copanlisib, CAI orotate, perifosine, RG-7666, GSK-2636771, DS-7423,panulisib, GSK-2269557, GSK-2126458, CUDC-907, PQR-309, INCB-40093,pilaralisib, BAY-1082439, puquitinib mesylate, SAR-245409, AMG-319,RP-6530, ZSTK-474, MLN-1117, SF-1126, RV-1729, sonolisib, LY-3023414,SAR-260301, TAK-117, HMPL-689, tenalisib, voxtalisib, and CLR-1401.

Indoleamine-2, 3-Dioxygenase (IDO) Pathway Inhibitors

Examples of IDO inhibitors include epacadostat (INCB24360), resminostat(4SC-201), indoximod, F-001287, SN-35837, NLG-919, GDC-0919, GBV-1028,GBV-1012, NKTR-218, and the compounds disclosed in US20100015178(Incyte).

PD-1 Inhibitors

Examples of PD-1 inhibitors include nivolumab, pembrolizumab,pidilizumab, BGB-108, SHR-1210, PDR-001, PF-06801591, IBI-308, GB-226,STI-1110, and mDX-400.

PD-L1 Inhibitors

Examples of PD-L1 inhibitors include atezolizumab, avelumab, AMP-224,MEDI-0680, RG-7446, GX-P2, durvalumab, KY-1003, KD-033, MSB-0010718C,TSR-042, ALN-PDL, STI-A1014, CX-072, and BMS-936559.

Recombinant Thymosin Alpha-1

Examples of recombinant thymosin alpha-1 include NL-004 and PEGylatedthymosin alpha-1.

Bruton's Tyrosine Kinase (BTK) Inhibitors

Examples of BTK inhibitors include ABBV-105, acalabrutinib (ACP-196),ARQ-531, BMS-986142, dasatinib, ibrutinib, GDC-0853, PRN-1008, SNS-062,ONO-4059, BGB-3111, ML-319, MSC-2364447, RDX-022, X-022, AC-058,RG-7845, spebrutinib, TAS-5315, TP-0158, TP-4207, HM-71224, KBP-7536,M-2951, TAK-020, AC-0025, and the compounds disclosed in US20140330015(Ono Pharmaceutical), US20130079327 (Ono Pharmaceutical), andUS20130217880 (Ono Pharmaceutical).

KDM Inhibitors

Examples of KDM5 inhibitors include the compounds disclosed inWO2016057924 (Genentech/Constellation Pharmaceuticals), US2014/0275092(Genentech/Constellation Pharmaceuticals), US20140371195(Epitherapeutics) and US20140371214 (Epitherapeutics), US2016/0102096(Epitherapeutics), US2014/0194469 (Quanticel), US2014/0171432,US2014/0213591 (Quanticel), US2016/0039808 (Quanticel), WO2014151945(Quanticel), WO2014164708 (Quanticel).

Examples of KDM1 inhibitors include the compounds disclosed in U.S. Pat.No. 9,186,337B2 (Oryzon Genomics), and GSK-2879552, RG-6016, ORY-2001.

HBV Replication Inhibitors

Examples of hepatitis B virus replication inhibitors includeisothiafludine, IQP-HBV, RM-5038, and Xingantie.

Arginase Inhibitors

Examples of Arginase inhibitors include CB-1158, C-201, and resminostat.

HBV Combination Therapy

In one embodiment, pharmaceutical compositions comprising a compounddisclosed herein, or a pharmaceutically acceptable salt thereof, incombination with one or more (e.g., one, two, three, four, one or two,or one to three, or one to four) additional therapeutic agents and apharmaceutically acceptable carrier, diluent, or excipient are provided.

HBV DNA Polymerase Inhibitor Combination Therapy

In a specific embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with an HBV DNApolymerase inhibitor. In another specific embodiment, a compounddisclosed herein, or a pharmaceutically acceptable salt thereof, iscombined with an HBV DNA polymerase inhibitor and at least oneadditional therapeutic agent selected from the group consisting of:immunomodulators, TLR modulators, interferon alpha receptor ligands,hyaluronidase inhibitors, recombinant IL-7, HBsAg inhibitors, HBsAgsecretion or assembly inhibitors, compounds targeting HBcAg, cyclophilininhibitors, HBV vaccines, HBV viral entry inhibitors, NTCP inhibitors,antisense oligonucleotide targeting viral mRNA, siRNA, miRNA genetherapy agents, endonuclease modulators, inhibitors of ribonucleotidereductase, hepatitis B virus E antigen inhibitors, recombinant SRAproteins, src kinase inhibitors, HBx inhibitors, cccDNA inhibitors,sshRNAs, HBV antibodies including HBV antibodies targeting the surfaceantigens of the hepatitis B virus and bispecific antibodies and“antibody-like” therapeutic proteins (such as DARTs®, DUOBODIES®,BITES®, XmAbs®, TandAbs®, Fab derivatives, or TCR-like antibodies), CCR2chemokine antagonists, thymosin agonists, cytokines, nucleoproteinmodulators (HBV core or capsid protein modulators), stimulators ofretinoic acid-inducible gene 1, stimulators of RIG-I like receptors,stimulators of NOD2, stimulators of NOD1, Arginase inhibitors, STINGagonists, PI3K inhibitors, lymphotoxin beta receptor activators, naturalkiller cell receptor 2B4 inhibitors, Lymphocyte-activation gene 3inhibitors, CD160 inhibitors, cytotoxic T-lymphocyte-associated protein4 (ipi4) inhibitors, CD137 inhibitors, Killer cell lectin-like receptorsubfamily G member 1 inhibitors, TIM-3 inhibitors, B- and T-lymphocyteattenuator inhibitors, CD305 inhibitors, PD-1 inhibitors, PD-L1inhibitors, PEG-Interferon Lambda, recombinant thymosin alpha-1, BTKinhibitors, modulators of TIGIT, modulators of CD47, modulators ofSIRPalpha, modulators of ICOS, modulators of CD27, modulators of CD70,modulators of OX40, epigenetic modifiers, modulators of NKG2D,modulators of Tim-4, modulators of B7-H4, modulators of B7-H3,modulators of NKG2A, modulators of GITR, modulators of CD160, modulatorsof HEVEM, modulators of CD161, modulators of Ax1, modulators of Mer,modulators of Tyro, gene modifiers or editors such as CRISPR (includingCRISPR Cas9), zinc finger nucleases or synthetic nucleases (TALENs),IAPs inhibitors, SMAC mimetics, KDM5 inhibitors, IDO inhibitors, andhepatitis B virus replication inhibitors.

In another specific embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with an HBV DNApolymerase inhibitor, one or two additional therapeutic agents selectedfrom the group consisting of immunomodulators, TLR modulators, HBsAginhibitors, HBsAg secretion or assembly inhibitors, HBV therapeuticvaccines, HBV antibodies including HBV antibodies targeting the surfaceantigens of the hepatitis B virus and bispecific antibodies and“antibody-like” therapeutic proteins (such as DARTs®, DUOBODIES®,BITES®, XmAbs®, TandAbs®, Fab derivatives, or TCR-like antibodies),cyclophilin inhibitors, stimulators of retinoic acid-inducible gene 1,stimulators of RIG-I like receptors, PD-1 inhibitors, PD-L1 inhibitors,Arginase inhibitors, PI3K inhibitors, IDO inhibitors, and stimulators ofNOD2, and one or two additional therapeutic agents selected from thegroup consisting of HBV viral entry inhibitors, NTCP inhibitors, HBxinhibitors, cccDNA inhibitors, HBV antibodies targeting the surfaceantigens of the hepatitis B virus, siRNA, miRNA gene therapy agents,sshRNAs, KDM5 inhibitors, and nucleoprotein modulators (HBV core orcapsid protein modulators).

In another specific embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with an HBV DNApolymerase inhibitor and at least a second additional therapeutic agentselected from the group consisting of: immunomodulators, TLR modulators,HBsAg inhibitors, HBV therapeutic vaccines, HBV antibodies including HBVantibodies targeting the surface antigens of the hepatitis B virus andbispecific antibodies and “antibody-like” therapeutic proteins (such asDARTs®, DUOBODIES®, BITES®, XmAbs®, TandAbs®, Fab derivatives, orTCR-like antibodies), cyclophilin inhibitors, stimulators of retinoicacid-inducible gene 1, stimulators of RIG-I like receptors, PD-1inhibitors, PD-L1 inhibitors, Arginase inhibitors, PI3K inhibitors, IDOinhibitors, and stimulators of NOD2.

In another specific embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with an HBV DNApolymerase inhibitor and at least a second additional therapeutic agentselected from the group consisting of: HBV viral entry inhibitors, NTCPinhibitors, HBx inhibitors, cccDNA inhibitors, HBV antibodies targetingthe surface antigens of the hepatitis B virus, siRNA, miRNA gene therapyagents, sshRNAs, KDM5 inhibitors, and nucleoprotein modulators (HBV coreor capsid protein inhibitors).

HBV Drug Combination Therapy

In a particular embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with a firstadditional therapeutic agent selected from the group consisting ofadefovir (HEPSERA®), tenofovir disoproxil fumarate (VIREAD®), tenofoviralafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamidefumarate, tenofovir alafenamide hemifumarate, entecavir (BARACLUDE®),telbivudine (TYZEKA®), or lamivudine (EPIVIR-HBV®), and at least asecond additional therapeutic agent selected from the group consistingof immunomodulators, TLR modulators, interferon alpha receptor ligands,hyaluronidase inhibitors, recombinant IL-7, HBsAg inhibitors, HBsAgsecretion or assembly inhibitors, compounds targeting HBcAg, cyclophilininhibitors, HBV vaccines, HBV viral entry inhibitors, NTCP inhibitors,antisense oligonucleotide targeting viral mRNA, siRNA, miRNA genetherapy agents, endonuclease modulators, inhibitors of ribonucleotidereductase, hepatitis B virus E antigen inhibitors, recombinant SRAproteins, src kinase inhibitors, HBx inhibitors, cccDNA inhibitors,sshRNAs, HBV antibodies including HBV antibodies targeting the surfaceantigens of the hepatitis B virus and bispecific antibodies and“antibody-like” therapeutic proteins (such as DARTs®, DUOBODIES®,BITES®, XmAbs®, TandAbs®, Fab derivatives, and TCR-like antibodies),CCR2 chemokine antagonists, thymosin agonists, cytokines, nucleoproteinmodulators (HBV core or capsid protein modulators), stimulators ofretinoic acid-inducible gene 1, stimulators of RIG-I like receptors,stimulators of NOD2, stimulators of NOD1, IDO inhibitors, recombinantthymosin alpha-1, Arginase inhibitors, STING agonists, PI3K inhibitors,lymphotoxin beta receptor activators, natural killer cell receptor 2B4inhibitors, Lymphocyte-activation gene 3 inhibitors, CD160 inhibitors,ipi4 inhibitors, CD137 inhibitors, killer cell lectin-like receptorsubfamily G member 1 inhibitors, TIM-3 inhibitors, B- and T-lymphocyteattenuator inhibitors, epigenetic modifiers, CD305 inhibitors, PD-1inhibitors, PD-L1 inhibitors, PEG-Interferon Lambd, BTK inhibitors,modulators of TIGIT, modulators of CD47, modulators of SIRPalpha,modulators of ICOS, modulators of CD27, modulators of CD70, modulatorsof OX40, modulators of NKG2D, modulators of Tim-4, modulators of B7-H4,modulators of B7-H3, modulators of NKG2A, modulators of GITR, modulatorsof CD160, modulators of HEVEM, modulators of CD161, modulators of Ax1,modulators of Mer, modulators of Tyro, gene modifiers or editors such asCRISPR (including CRISPR Cas9), zinc finger nucleases or syntheticnucleases (TALENs), IAPs inhibitors, SMAC mimetics, KDM5 inhibitors, andhepatitis B virus replication inhibitors.

In a particular embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with a firstadditional therapeutic agent selected from the group consisting ofadefovir (HEPSERA®), tenofovir disoproxil fumarate (VIREAD®), tenofoviralafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamidefumarate, tenofovir alafenamide hemifumarate, entecavir (BARACLUDE®),telbivudine (TYZEKA®) or lamivudine (EPIVIR-HBV®) and at least a secondadditional therapeutic agent selected from the group consisting ofpeginterferon alfa-2b (PEG-INTRON®), MULTIFERON®, interferon alpha 1b(HAPGEN®), interferon alpha-2b (INTRON A®), pegylated interferonalpha-2a (PEGASYS®), interferon alfa-n1 (HUMOFERON®), ribavirin,interferon beta-1a (AVONEX®), Bioferon, Ingaron, Inmutag (Inferon),Algeron, Roferon-A, Oligotide, Zutectra, Shaferon, interferon alfa-2b(AXXO), Alfaferone, interferon alfa-2b (BioGeneric Pharma), Feron,interferon-alpha 2 (CJ), BEVAC, Laferonum, VIPEG, BLAUFERON-B,BLAUFERON-A, Intermax Alpha, Realdiron, Lanstion, Pegaferon, PDferon-B,interferon alfa-2b (IFN, Laboratorios Bioprofarma), alfainterferona 2b,Kalferon, Pegnano, Feronsure, PegiHep, interferon alfa 2b(Zydus-Cadila), Optipeg A, Realfa 2B, Reliferon, interferon alfa-2b(Amega), interferon alfa-2b (Virchow), peginterferon alfa-2b (Amega),Reaferon-EC, Proquiferon, Uniferon, Urifron, interferon alfa-2b(Changchun Institute of Biological Products), Anterferon, Shanferon,MOR-22, interleukin-2 (IL-2, Immunex), recombinant human interleukin-2(Shenzhen Neptunus), Layfferon, Ka Shu Ning, Shang Sheng Lei Tai,INTEFEN, SINOGEN, Fukangtai, Alloferon, and celmoleukin.

In a particular embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with a firstadditional therapeutic agent selected from the group consisting ofadefovir (HEPSERA®), tenofovir disoproxil fumarate (VIREAD®), tenofoviralafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamidefumarate, tenofovir alafenamide hemifumarate, entecavir (BARACLUDE®),telbivudine (TYZEKA®), or lamivudine (EPIVIR-HBV®), and at least asecond additional therapeutic agent selected from the group consistingof immunomodulators, TLR modulators, HBsAg inhibitors, HBsAg secretionor assembly inhibitors, HBV therapeutic vaccines, HBV antibodiesincluding HBV antibodies targeting the surface antigens of the hepatitisB virus and bispecific antibodies and “antibody-like” therapeuticproteins (such as DARTs®, DUOBODIES®, BITES®, XmAbs®, TandAbs®, Fabderivatives, or TCR-like antibodies), cyclophilin inhibitors,stimulators of retinoic acid-inducible gene 1, stimulators of RIG-I likereceptors, Arginase inhibitors, PI3K inhibitors, PD-1 inhibitors, PD-L1inhibitors, IDO inhibitors and stimulators of NOD2.

In a particular embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with a firstadditional therapeutic agent selected from the group consisting of:adefovir (HEPSERA®), tenofovir disoproxil fumarate (VIREAD®), tenofoviralafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamidefumarate, tenofovir alafenamide hemifumarate, entecavir (BARACLUDE®),telbivudine (TYZEKA®), or lamivudine (EPIVIR-HBV®), and at least asecond additional therapeutic agent selected from the group consistingof HBV viral entry inhibitors, NTCP inhibitors, HBx inhibitors, cccDNAinhibitors, HBV antibodies targeting the surface antigens of thehepatitis B virus, siRNA, miRNA gene therapy agents, sshRNAs, KDM5inhibitors, and nucleoprotein modulators (HBV core or capsid proteinmodulators).

In a particular embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with a firstadditional therapeutic agent selected from the group consisting ofadefovir (HEPSERA®), tenofovir disoproxil fumarate (VIREAD®), tenofoviralafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamidefumarate, tenofovir alafenamide hemifumarate, entecavir (BARACLUDE®),telbivudine (TYZEKA®), or lamivudine (EPIVIR-HBV®); one, two, or threeadditional therapeutic agents selected from the group consisting ofimmunomodulators, TLR modulators, HBsAg inhibitors, HBsAg secretion orassembly inhibitors, HBV therapeutic vaccines, HBV antibodies includingHBV antibodies targeting the surface antigens of the hepatitis B virusand bispecific antibodies and “antibody-like” therapeutic proteins (suchas DARTs®, DUOBODIES®, BITES®, XmAbs®, TandAbs®, Fab derivatives, orTCR-like antibodies), cyclophilin inhibitors, stimulators of retinoicacid-inducible gene 1, stimulators of RIG-I like receptors, PD-1inhibitors, PD-L1 inhibitors, Arginase inhibitors, PI3K inhibitors, IDOinhibitors, and stimulators of NOD2; and one or two additionaltherapeutic agents selected from the group consisting of HBV viral entryinhibitors, NTCP inhibitors, HBx inhibitors, cccDNA inhibitors, HBVantibodies targeting the surface antigens of the hepatitis B virus,siRNA, miRNA gene therapy agents, sshRNAs, KDM5 inhibitors, andnucleoprotein modulators (HBV core or capsid protein modulators).

In a particular embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with a firstadditional therapeutic agent selected from the group consisting ofadefovir (HEPSERA®), tenofovir disoproxil fumarate (VIREAD®), tenofoviralafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamidefumarate, tenofovir alafenamide hemifumarate, entecavir (BARACLUDE®),telbivudine (TYZEKA®), or lamivudine (EPIVIR-HBV®); one or twoadditional therapeutic agents selected from the group consisting ofimmunomodulators, TLR modulators, HBsAg inhibitors, HBsAg secretion orassembly inhibitors, HBV therapeutic vaccines, HBV antibodies includingHBV antibodies targeting the surface antigens of the hepatitis B virusand bispecific antibodies and “antibody-like” therapeutic proteins (suchas DARTs®, DUOBODIES®, BITES®, XmAbs®, TandAbs®, Fab derivatives, orTCR-like antibodies), cyclophilin inhibitors, stimulators of retinoicacid-inducible gene 1, stimulators of RIG-I like receptors, PD-1inhibitors, PD-L1 inhibitors, Arginase inhibitors, PI3K inhibitors, IDOinhibitors, and stimulators of NOD2; and one or two additionaltherapeutic agents selected from the group consisting of HBV viral entryinhibitors, NTCP inhibitors, HBx inhibitors, cccDNA inhibitors, HBVantibodies targeting the surface antigens of the hepatitis B virus,siRNA, miRNA gene therapy agents, sshRNAs, KDM5 inhibitors, andnucleoprotein modulators (HBV core or capsid protein modulators).

In a particular embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with a firstadditional therapeutic agent selected from the group consisting ofadefovir (HEPSERA®), tenofovir disoproxil fumarate (VIREAD®), tenofoviralafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamidefumarate, tenofovir alafenamide hemifumarate, entecavir (BARACLUDE®),telbivudine (TYZEKA®), or lamivudine (EPIVIR-HBV®); and one, two, three,or four additional therapeutic agents selected from the group consistingof immunomodulators, TLR7 modulators, TLR8 modulators, HBsAg inhibitors,HBsAg secretion or assembly inhibitors, HBV therapeutic vaccines, HBVantibodies including HBV antibodies targeting the surface antigens ofthe hepatitis B virus and bispecific antibodies and “antibody-like”therapeutic proteins (such as DARTs®, DUOBODIES®, BITES®, XmAbs®,TandAbs®, Fab derivatives, or TCR-like antibodies), cyclophilininhibitors, stimulators of retinoic acid-inducible gene 1, stimulatorsof RIG-I like receptors, PD-1 inhibitors, PD-L1 inhibitors, Arginaseinhibitors, PI3K inhibitors, IDO inhibitors, stimulators of NOD2 HBVviral entry inhibitors, NTCP inhibitors, HBx inhibitors, cccDNAinhibitors, siRNA, miRNA gene therapy agents, sshRNAs, KDM5 inhibitors,and nucleoprotein modulators (HBV core or capsid protein modulators).

In certain embodiments, a compound as disclosed herein (e.g., anycompound of Formula I) may be combined with one or more (e.g., one, two,three, four, one or two, one to three, or one to four) additionaltherapeutic agents in any dosage amount of the compound of Formula I(e.g., from 10 mg to 1000 mg of compound).

In certain embodiments, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with 5-30 mgtenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, ortenofovir alafenamide. In certain embodiments, a compound disclosedherein, or a pharmaceutically acceptable salt thereof, is combined with5-10; 5-15; 5-20; 5-25; 25-30; 20-30; 15-30; or 10-30 mg tenofoviralafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofoviralafenamide. In certain embodiments, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with 10 mgtenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, ortenofovir alafenamide. In certain embodiments, a compound disclosedherein, or a pharmaceutically acceptable salt thereof, is combined with25 mg tenofovir alafenamide fumarate, tenofovir alafenamidehemifumarate, or tenofovir alafenamide. A compound as disclosed herein(e.g., a compound of Formula I) may be combined with the agents providedherein in any dosage amount of the compound (e.g., from 50 mg to 500 mgof compound) the same as if each combination of dosages werespecifically and individually listed.

In certain embodiments, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with 100-400 mgtenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, ortenofovir disoproxil. In certain embodiments, a compound disclosedherein, or a pharmaceutically acceptable salt thereof, is combined with100-150; 100-200, 100-250; 100-300; 100-350; 150-200; 150-250; 150-300;150-350; 150-400; 200-250; 200-300; 200-350; 200-400; 250-350; 250-400;350-400 or 300-400 mg tenofovir disoproxil fumarate, tenofovirdisoproxil hemifumarate, or tenofovir disoproxil. In certainembodiments, a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, is combined with 300 mg tenofovir disoproxilfumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil. Incertain embodiments, a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, is combined with 250 mg tenofovir disoproxilfumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil. Incertain embodiments, a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, is combined with 150 mg tenofovir disoproxilfumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil. Acompound as disclosed herein (e.g., an inhibitor of NS5A or NS5B) may becombined with the agents provided herein in any dosage amount of thecompound (e.g., from 50 mg to 500 mg of compound) the same as if eachcombination of dosages were specifically and individually listed.

In one embodiment, kits comprising a compound disclosed herein, or apharmaceutically acceptable salt thereof, in combination with one ormore (e.g., one, two, three, four, one or two, or one to three, or oneto four) additional therapeutic agents are provided.

VII. EXAMPLES Example 1: Antiviral Activity

Another aspect of the disclosure relates to methods of inhibiting viralinfections, comprising the step of treating a sample or subjectsuspected of needing such inhibition with a composition of thedisclosure.

Within the context of the disclosure samples suspected of containing avirus include natural or man-made materials such as living organisms;tissue or cell cultures; biological samples such as biological materialsamples (blood, serum, urine, cerebrospinal fluid, tears, sputum,saliva, tissue samples, and the like); laboratory samples; food, water,or air samples; bioproduct samples such as extracts of cells,particularly recombinant cells synthesizing a desired glycoprotein; andthe like. Typically the sample will be suspected of containing anorganism which induces a viral infection, frequently a pathogenicorganism such as a tumor virus. Samples can be contained in any mediumincluding water and organic solvent\water mixtures. Samples includeliving organisms such as humans, and manmade materials such as cellcultures.

If desired, the anti-virus activity of a compound of the disclosureafter application of the composition can be observed by any methodincluding direct and indirect methods of detecting such activity.Quantitative, qualitative, and semiquantitative methods of determiningsuch activity are all contemplated. Typically one of the screeningmethods described above are applied, however, any other method such asobservation of the physiological properties of a living organism arealso applicable.

The antiviral activity of a compound of the disclosure can be measuredusing standard screening protocols that are known.

Example 2: Evaluation of Cell-Based Anti-HCV Activity

In order to evaluate a compound's ability to inhibit NS5A, NS5B or NS3,the following protocol may be employed.

Cell-Based NSSA Assay

Antiviral potency (EC₅₀) is determined using a Renilla luciferase(RLuc)-based HCV replicon reporter assay. To perform the assay forgenotype 1 and 2a JFH-1, stable HCV 1a RLuc replicon cells (harboring adicistronic genotype 1a H77 replicon that encodes a RLuc reporter),stable HCV 1b RLuc replicon cells (harboring a dicistronic genotype 1bCon1 replicon that encodes a RLuc reporter), or stable HCV 2a JFH-1 Rlucreplicon cells (harboring a dicistronic genotype 2a JFH-1 replicon thatencodes a RLuc reporter; with L31 present in NS5A) are dispensed into384-well plates for EC₅₀ assays. To perform the assay for genotype 2a(with M31 present in NS5A) or genotype 2b, NS5A chimeric genotype 2aJFH-1 replicons that encodes a RLuc-Neo reporter and either genotype 2aJ6 strain NS5A gene or genotype 2b MD2b-1 strain NS5A gene (both withM31 present) respectively, are either transiently transfected (t) intoHuh-Lunet cells or are established as stably replicating repliconcells(s). Either cells are dispensed into 384-well plates for EC₅₀assays. To perform the assay for genotype 3 and genotype 4, NS5Achimeric genotype 1b Con1 replicons that encodes a Pi-RLuc reporter andeither genotype 3a S52 strain NS5A gene or genotype 4a ED43 strain NS5Agene respectively, are transiently transfected (t) into Huh-Lunet cells,which are subsequently dispensed into 384-well plates. Compounds aredissolved in DMSO at a concentration of 10 mM and diluted in DMSO eithermanually or using an automated pipetting instrument. Serially 3-folddiluted compounds are either manually mixed with cell culture media andadded to the seeded cells or directly added to the cells using anautomated instrument. DMSO is used as a negative (solvent; noinhibition) control, and the protease inhibitor ITMN-191 is included ata concentration >100×EC₅₀ as a positive control. 72 hours later, cellsare lysed and Renilla luciferase activity quantified as recommended bythe manufacturer (Promega-Madison, Wis.). Non-linear regression wasperformed to calculate EC₅₀ values.

To determine the antiviral potency (EC₅₀) against resistance mutants,resistance mutations, including M28T, Q30R, Q30H, L31M, and Y93C ingenotype 1a NS5A and Y93H in genotype 1b NS5A, are introducedindividually into either 1a Pi-Rluc or 1b Pi-Rluc replicons by sitedirected mutagenesis. Replicon RNA of each resistant mutant wastransiently transfected into Huh-7-derived cured-51 cells and antiviralpotency is determined on these transfected cells as described above.

Cell-Based NS5B Assay

Each compound (serially diluted from 100 μM) is added to Huh7 (2×10³cells/well), HepG2 (2×10³ cells/well), BxPC3 (2×10³ cells/well), or CEM(5×10³ cells/well) cells and allowed to incubate for 8 days at 37° C. Amedium only control is used to determine the minimum absorbance valueand an untreated cell. At the end of the growth period, MTS dye from theCellTiter 96 Aqueous One Solution Cell Proliferation Assay kit (Promega)is added to each well and the plate is incubated for an additional 2hours. The absorbance at 490 nm is read with a Victor 3 plate reader(Perkin Elmer) using the medium only control wells as blanks. The 50%inhibition value (CC₅₀) is determined by comparing the absorbance inwells containing cells and test compound to untreated cell controlwells.

The HCV NS5B reaction is performed in a 20 μL mixture containing varyingconcentrations of the test compound, 1 μM of all four naturalribonucleotides, [α-³²P]UTP, 20 ng/μL of genotype 1b (−) IRES RNAtemplate, 1 unit/μL of SUPERase⋅In (Ambion, Austin, Tex.), 40 ng/μL ofwild type or S282T NS5B Genotype 1b, 1 mM MgCl₂, 0.75 mM MnCl₂, and 2 mMDTT in 50 mM Hepes buffer (pH 7.5). The reaction is quenched by adding80 μL of stop solution (12.5 mM EDTA, 2.25 M NaCl, and 225 mM sodiumcitrate) after incubating at 27° C. for 30 minutes. The radioactive RNAproducts are separated from unreacted substrates by passing the quenchedreaction mixture through a Hybond N+ membrane (GE Healthcare,Piscataway, N.J.) using a dot-blot apparatus. The RNA products areretained on the membrane and the free nucleotides are washed out. Themembrane is washed 4 times with a solution containing 0.6 M NaCl and 60mM sodium citrate. After rinsing the membrane with water followed byethanol, the membrane is exposed to a phosphorscreen and the productsare visualized and quantified using a phosphorimager. The IC₅₀ valuesare calculated using GraFit program version 5 (Erithacus Software,Horley, Surrey, UK). All the reactions are done in duplicate and theresults are reported as IC₅₀±standard error.

Cell-Based NS3 Assay

Antiviral potency (EC₅₀) is determined in both stable subgenomic HCVreplicon cell lines and transient-transfected HCV replicon cells. Theterm half maximal effective concentration (EC₅₀) refers to theconcentration of a drug which induces a response halfway between thebaseline and maximum after the exposure time specified.

Stable subgenomic HCV replicons for genotype 1a, 1b, 2a, 3a, and 4a areestablished in Huh-7-derived cells as described by Lohmann et al(Lohmann V, Korner F, Koch J, et al Replication of subgenomic hepatitisC virus RNAs in a hepatoma cell line, Science 1999; 285:119-3). Eachstable cell line contains a bicistronic HCV replicon that encodes ahumanized Renilla luciferase (hRLuc) reporter gene fused to a selectableneomycin-resistance gene, followed by an EMCV IRES and the NS3-NS5Bcoding region of HCV. Selection for cells constitutively expressing theHCV replicon is achieved in the presence of the selection antibiotic,neomycin (G418). Luciferase activity is measured as a marker forintracellular HCV replication levels.

The genotype 1a stable replicon is derived from the H77 HCV strain andcontained adaptive mutations P1496L and S2204I. The genotype 1b stablereplicon is derived from the Con1 HCV strain and contained adaptivemutations E1202G, T12801, and K1846T. The genotype 2a stable replicon isderived from the JFH-1 HCV strain and does not require adaptivemutations. The genotype 3a stable replicon is derived from the S52 HCVstrain and contained adaptive mutations P1121L, A1198T and S2210I(equivalent to S2204I in genotype 1). The genotype 4a stable replicon isderived from the ED43 HCV strain and contained adaptive mutations Q1691Rand S2204I. All replicon cell lines were propagated in Huh-7-derivedcells and maintained in Dulbecco's modified Eagle's Medium (DMEM)supplemented with 10% fetal bovine serum (FBS) and 0.5 mg/ml G418.

Transient-transfected HCV replicons are established for genotype 1a, 1b,3a and NS3/4a protease inhibitor resistant variants D168A in genotype 1bor R155K in genotype 1a. Transient-transfected replicons are alsobiscistronic subgenomic replicons but do not contain the neomycinselectable marker present in stable replicons. These replicons encodethe poliovirus IRES followed by the hRLuc reporter gene, the EMCV IRESand finally the NS3-NS5B coding region of HCV. The genotype 1a (H77) and1b (Con1) wild-type replicons are derived from the same strain andcontain the same adaptive mutations as listed above. The genotype 3atransient replicon is derived from the S52 HCV strain as above, butcontains slightly different adaptive mutations P1112L, K1615E and52210I. Specifically, the secondary adaptive mutation A1198T (A166T) inthe protease domain of the stable genotype 3a replicon is replaced withK1615E (K583E) in the NS3 helicase, with no effect on replicationefficiency. Removal of A166T located in the protease domain minimizesthe impact of this variant on inhibitors targeting the protease domainand represents a protease domain closer to wild type for genotype 3a.Resistant replicons encoding NS3/4 protease inhibitor mutations areintroduced into the 1b or 1a wild-type NS3 gene by site directedmutagenesis. In vitro transcribed RNAs from all transient replicons aretransfected into naive Huh-7-derived cell lines by electroporation.Luciferase activity is measured as a marker for intracellular HCVreplication levels.

To perform EC₅₀ assays, cells from each HCV replicon are dispensed into384-well plates. Compound(s) are dissolved in DMSO at a concentration of10 mM and diluted in DMSO using an automated pipetting instrument.Three-fold serially diluted compounds are directly added to the cellsusing an automated instrument. DMSO is used as a negative (solvent; noinhibition) control, and a combination of three HCV inhibitors includinga protease inhibitor; an NS5A inhibitor and a nucleoside inhibitor isused at concentrations >100×EC₅₀ as a positive control (100%inhibition). Seventy-two hours later, cells are lysed and Renillaluciferase activity are quantified as recommended by the manufacturer(Promega-Madison, Wis.). Non-linear regression is performed to calculateEC₅₀ values.

Example 3. Reduction of Hepatitis B Surface Antigen

Inhibitors described herein are tested for their ability to reducehepatitis B surface antigen (HBsAg) based on the following protocol.

HBV Cell Line

HepG2.2.15 cells (Acs et al. Proc Natl Acad Sci USA, 84, (1987),4641-4), a constitutively HBV-expressing cell line are cultured inDMEM+Glutamax-I medium (Invitrogen, Carlsbad, Calif., USA), supplementedwith 10% fetal bovine serum (Invitrogen) and G418 (Invitrogen) at afinal concentration of 200 mg/L and maintained in 5% CO₂ at 37° C.

HBsAg Assay

HepG2.2.15 cells are seeded in duplicate into white, 96-well plates at1.5×10 cells/well. The cells are treated with a three-fold serialdilution series of the compounds in DMSO. The final DMSO concentrationin all wells is 1% and DMSO is used as no drug control.

The HBsAg chemiluminescence immunoassay (CLIA) kit (Autobio DiagnosticsCo., Zhengzhou, China, Catalog number: CL0310-2) is used to measure thelevels of secreted HBV antigens semi-quantitatively. For the detection50 μL well culture supernatant is used and HBsAg is quantified usingHBsAg chemiluminescence immunoassay (CLIA) kit (Autobio Diagnostics Co.,Zhengzhou, China, Catalog number: C 1.0310-2), 50 μL of the supernatantis transferred to the CLIA assay plate and 50 μL of enzyme conjugatereagent is added into each well. The plates are sealed and gentlyagitated for 1 hour at room temperature. The supernatant-enzyme-mixtureis discarded and wells are washed 6 times with 300 μL of PBS. Theresidual liquid is removed by plating the CLIA plate right side down onabsorbent tissue paper. 25 μL of substrates A and B were added to eachwell. Luminance is measured using a luminometer (Mithras LB 940Multimode Microplate Reader) after 10 minutes incubation. Dose responsecurves are generated and the IC₅₀ value is extrapolated by using theE-WorkBook Suite (ID Business Solutions Ltd., Guildford, UK). The IC₅₀is defined as the compound concentration (or conditioned media logdilution) at which HBsAg secretion is reduced by 50% compared to the nodrug control.

Example 4. HBV DNA Assay

A HBV DNA assay may also be employed to evaluate a test compound'sactivity in inhibiting HBV DNA replication. The assay employs real-timeqPCR (Taq an) to directly measure extracellular HBV DNA copy number.HepG2.2.15 cells are plated in 96-well microtiter plates. On thefollowing day, the HepG2.2. 1 5 cells are washed and the medium isreplaced with complete medium containing various concentrations of atest compound in triplicate. 3TC is used as the positive control, whilemedia alone is added to cells as a negative control (virus control, VC).Three days later, the culture medium is replaced with fresh mediumcontaining the appropriately diluted drug. Six days following theinitial administration of the test compound, the cell culturesupernatant is collected, treated with pronase and then used in areal-time qPCR/TaqMan assay to determine HBV DNA copy numbers. Antiviralactivity is calculated from the reduction in HBV DNA levels (IC₅₀).

Example 5. HBV Reduction in Patients

Efficacy may be tested in human patients according to a variety ofprotocols known in the art, such as Kim et al., “HBsAg level andclinical course in patients with chronic hepatitis B treated withnucleoside analogue: five years of follow-up data,” Clin. Mol Hepatol.,2013, 19(4), 409-416 or Lee et al., “Quantitative hepatitis B surfaceantigen and hepatitis B e entigen titers in prediction of treatmentresponse to entecavir, Hepatology, 2011, 53, 1486-1493.

Further, the Architect HBsAg quantitative kit is also available forpurchase from Abbott Laboratories. The assay method is described below.

Methods

The ARCHITECT HBsAg assay is a two-step immunoassay, usingchemiluminescent microparticle immunoassay (CMIA) technology, withflexible assay protocols, referred to as Chemiflex for the quantitativedetermination of HBsAg in human serum. In the first step, samples andanti-HBs coated paramagnetic microparticles are combined HBsAg presentin the sample binds to the anti-HBs coated microparticles. Afterwashing, acridinium-labeled anti-HBs conjugate is added in the secondstep. Following another wash cycle, Pre-trigger and Trigger Solutionsare added to the reaction mixture. The resulting chemiluminescentreaction is measured as relative light units (RLUs). A directrelationship exists between the amount of HBsAg in the sample and theRLUs detected by the ARCHITECT i System optics.

The concentration of hepatitis B surface antigen in the specimen isdetermined using a previously generated ARCHITECT HBsAg calibrationcurve. If the concentration of the specimen is greater than or equal to0.05 IU/mL, the specimen is considered reactive for HBsAg.

Specimen

Testing is performed on human serum. A minimum volume of 0.35 mL isrequested. Specimens are shipped to Covance frozen on dry ice and arestable for 90 days at −70 C. The stability ambient is 3 days and thestability refrigerated is 7 days. Hepatitis B Surface Ag Quantitativetesting has 5 days TAT and it is performed at the Geneva and SingaporeCCLS facility.

Reagent

The ARCHITECT HBsAg Quantitative Reagent kit assay is manufactured byAbbott Ireland Diagnostic Division, Ireland.

Calibration

Abbott Laboratories provides the two HBsAg calibrators. A two-pointcalibration is performed once every six months, whenever a lot numberchange occurs or major system components are replaced.

Intra-Assay Precision

The manufacturer states expected intra-assay precision for HBsAgquantitative as 4.1-7.8% CV. The acceptable limit for CCLS is less thanor equal to 6.9% CV. The following shows intra-assay precisiondetermined by two quality controls tested in single run then evaluatingthe coefficient of variation (Statement of Claims Summary Report, May2014):

QC II QC III Mean (IU/mL) 0.252 165.840 SD 0.011 6.336 % CV 4.2% 3.8% N20 20Intra-Assay Precision

The manufacturer states expected inter-assay precision values for HBsAgquantitative as 6.2-9.2%. The acceptable limit CCLS is less than orequal to 9.1% CV. The following shows inter-assay precision determinedby analysis of quality control material (May 2014):

QC II QC III Mean (IU/mL) 0.249 165.797 SD 0.007 10.429 % CV 3.0% 6.3% N10 10Accuracy

Accuracy is an important parameter in the validation process. Forcertain assays, accuracy is assessed using standard validated referencematerials (SVRM's) or primary reference materials that are availablefrom the College of American Pathologists (CAP), and other sources suchas National Institute of Standards and Technology (NIST) and othersuppliers. In other cases, the results from proficiency testing (PT)that are obtained from agencies such as the CAP or other PT providersare used to establish accuracy. The example may also establish anaccuracy statement using either assayed quality control samples providedfrom commercial sources or a split specimen study with a qualifiedreference laboratory or another laboratory.

Reportable Range

The reportable range for the HBsAg quantitative assay is 0.05-125000.00IU/mL. The analytical measurement range is 0.05-250.00 IU/mL. Sampleswith HBsAg concentrations greater than 250.00 IU/mL are diluted up to amaximum dilution of 1:500, extending the upper reporting limit to125000.00 IU/mL.

Specificity and Sensitivity

The assay is unaffected by icterus (bilirubin <342 μmol/L or <20 mg/dL),hemolysis (Hgb <0.311 mmol/L or <0.5 g/dL), lipemia (triglycerides<33.87 mmol/L or <3000 mg/dL), and protein <12 g/dL. In patientsreceiving therapy with biotin doses (i.e. >5 mg/day), no samples shouldbe taken until at least 8 hours after the last biotin administration.

Results

Overall Specificity and Sensitivity

Overall specificity and sensitivity were estimated from the results of6429 serum and plasma specimens, tested with ARCHITECT HBsAg at sixclinical sites. HBV seroconversion panels results were excluded fromthis calculation because the panels contained multiple bleeds from thesame individual. Only the plasma specimens from the matched serum/plasmapairs were used so that these specimens would be represented once.

The overall specificity was estimated to be 99.87% (6001/6009) with a95% confidence interval of 99.74% to 99.94%. The overall sensitivity wasestimated to be 99.52% (418/420) with a 95% confidence interval of98.29% to 99.94%.

HBsAg Mutant Detection

HBsAg mutant susceptibility was evaluated with the ARCHITECT HBsAgassay.

The most prevalent HBsAg mutant, the Gly→Arg 145 mutant (Glycine [GLY]to Arginine [ARG] mutation at amino acid position 145 of HBsAg), wasreadily detected in the ARCHITECT HBsAg assay with a sensitivityequivalent to detection of wild type HBsAg30.

As can be seen in FIG. 1 , after administration of a fixed dosecombination of ledipasvir (90 mg) and sofosbuvir (400 mg) once daily,patients saw a reduction in HBsAg. This data was observed based on theclinical trial evaluating safety and efficacy of ledipasvir/sofosbuvirfixed dose combination in adults with chronic HCV and HBV co-infection.The patients were dosed for 12 weeks and suffered from chronic genotype1 or 2 HCV and HBV.

Additional data acquired after administration of the combination areseen in FIGS. 2-4 . As shown in FIG. 2 , at week 8, the patients hadmore pronounced reduction of HBsAg than at week 4. The overall trend ofthe HBsAg reduction over the treatment period is apparent from FIG. 3 ,while there are more variabilities in the reduction of mean HBV DNAamounts. The changes of HBsAg in each individual patient are plotted inFIG. 4 , and it can be seen that there is a universal reduction of HBsAglevels among all patients over time.

All publications, patents, and patent documents cited herein above areincorporated by reference herein, as though individually incorporated byreference.

The disclosure has been described with reference to various specific andpreferred embodiments and techniques. However, one skilled in the artwill understand that many variations and modifications may be made whileremaining within the spirit and scope of the disclosure.

What is claimed is:
 1. A method for treating a hepatitis B virusinfection in a human in need thereof comprising administering aneffective amount of ledipasvir and an effective amount of sofosbuvir andoptionally a NS3 inhibitor, wherein the effective amount of ledipasvirand the effective amount of sofosbuvir is sufficient to lower the HBsAglevel in the human.
 2. The method of claim 1, wherein the human isadministered about 90 milligrams of ledipasvir.
 3. The method of claim1, wherein the human is administered about 400 milligrams of sofosbuvir.4. The method of claim 1, wherein the NS3 inhibitor is voxilaprevir. 5.The method of claim 1, wherein ledipasvir and sofosbuvir and optionallythe NS3 inhibitor are administered together.
 6. The method of claim 1,wherein ledipasvir and sofosbuvir and optionally the NS3 inhibitor areadministered separately.
 7. The method of claim 1, further comprisingadministering to the human an effective amount of a reversetranscriptase inhibitor.
 8. The method of claim 7, wherein the reversetranscriptase inhibitor is tenofovir alafenamide.
 9. The method of claim8, wherein the human is administered about 25 mg tenofovir alafenamide.10. The method of claim 1, wherein the human is co-infected with humanimmunodeficiency virus (HIV).
 11. The method of claim 1, wherein thehuman is not co-infected with hepatitis C virus (HCV).
 12. A method fortreating a hepatitis B virus infection in a human in need thereofcomprising administering an effective amount of ledipasvir and aneffective amount of sofosbuvir and optionally a NS3 inhibitor, whereinthe human is not co-infected with hepatitis C virus (HCV).
 13. Themethod of claim 12, wherein the human is administered about 90milligrams of ledipasvir.
 14. The method of claim 12, wherein the humanis administered about 400 milligrams of sofosbuvir.
 15. The method ofclaim 12, wherein the NS3 inhibitor is voxilaprevir.
 16. The method ofclaim 12, wherein ledipasvir and sofosbuvir and optionally the NS3inhibitor are administered together.
 17. The method of claim 12, whereinledipasvir and sofosbuvir and optionally the NS3 inhibitor areadministered separately.
 18. The method of claim 12, further comprisingadministering to the human an effective amount of a reversetranscriptase inhibitor.
 19. The method of claim 18, wherein the reversetranscriptase inhibitor is tenofovir alafenamide.
 20. The method ofclaim 19, wherein the human is administered about 25 mg tenofoviralafenamide.
 21. The method of claim 12, wherein the human isco-infected with human immunodeficiency virus (HIV).